Overview of Recent Strategic Advances in Medicinal Chemistry
- Gaochan WuGaochan WuDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Gaochan Wu,
- Tong ZhaoTong ZhaoDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Tong Zhao,
- Dongwei KangDongwei KangDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Dongwei Kang,
- Jian ZhangJian ZhangDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Jian Zhang,
- Yuning SongYuning SongDepartment of Clinical Pharmacy, Qilu Hospital of Shandong University, 250012 Ji’nan, ChinaMore by Yuning Song,
- Vigneshwaran NamasivayamVigneshwaran NamasivayamPharmaceutical Institute, Pharmaceutical Chemistry II, University of Bonn, 53121 Bonn, GermanyMore by Vigneshwaran Namasivayam,
- Jacob KongstedJacob KongstedDepartment of Physics, Chemistry, and Pharmacy, University of Southern Denmark, DK-5230 Odense M, DenmarkMore by Jacob Kongsted,
- Christophe PannecouqueChristophe PannecouqueRega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, BelgiumMore by Christophe Pannecouque,
- Erik De ClercqErik De ClercqRega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, BelgiumMore by Erik De Clercq,
- Vasanthanathan Poongavanam*Vasanthanathan Poongavanam*(V.P.) E-mail: [email protected]Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, DK-5230 Odense M, DenmarkMore by Vasanthanathan Poongavanam,
- Xinyong Liu*Xinyong Liu*(X.L.) E-mail: [email protected]. Phone: 086-531-88380270.Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Xinyong Liu, and
- Peng Zhan*Peng Zhan*(P.Z.) E-mail: [email protected]. Phone: 086-531-88382005.Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. ChinaMore by Peng Zhan
Copyright © 2019 American Chemical Society
Abstract
Introducing novel strategies, concepts, and technologies that speed up drug discovery and the drug development cycle is of great importance both in the highly competitive pharmaceutical industry as well as in academia. This Perspective aims to present a “big-picture” overview of recent strategic innovations in medicinal chemistry and drug discovery.
Introduction
ARTICLE SECTIONS
The process of drug development, from identification of a new bioactive chemical entity to regulatory approval, is complex, costly, and time-consuming. It can take 10–15 years or even longer.(1−3) Thus, there is enormous pressure from the pharmaceutical industry, as well as clinicians and patients, to speed up the process. Fortunately, the extremely rapid accumulation of biological data in the postgenomic era as well as the development of computational chemical biology have stimulated an unprecedented revolution in medicinal chemistry, and the paradigm for discovery of pharmacologically interesting molecules has changed over the past few decades from a largely serendipitous, trial-and-error approach to a much more sophisticated and multifaceted approach, which has greatly improved the efficiency of drug discovery resulting in a significant acceleration of the overall process.(4−7)
This current Perspective analyzes the articles that have appeared recently in some top journals of the medicinal chemistry community (primarily in the Journal of Medicinal Chemistry), in order to provide a broad-brush picture of the trends in strategic innovations in the fields of medicinal chemistry, drug discovery, and other related fields (Figure 1), focusing in particular on drug repurposing, diversity-oriented synthesis-facilitated medicinal chemistry, structure-based drug discovery, multiparameter optimization, and biological system-mediated drug delivery. The strategy of bioorthogonal chemistry and photoactivatable-inspired medicinal chemistry with high temporal and spatial precision was first proposed by integrating related innovations in related fields.
Figure 1
Figure 1. Overview of recent strategic advances in medicinal chemistry.
1. Drug Repurposing and “Privileged Structure” Repositioning
ARTICLE SECTIONS
Drug repurposing (also called repositioning, redirecting, reprofiling) is a polypharmacology-driven strategy for generating additional value from an existing drug by targeting diseases other than that for which it was originally intended.(8,9) This has significant advantages over new drug discovery since chemical synthesis steps, manufacturing processes, reliable safety, and pharmacokinetic properties in early clinical developmental phases (Phase I and Phase IIa trials) are already available. Therefore, repositioning of launched or even failed drugs provides unique translational opportunities, including a substantially higher probability of success to market as compared with new drugs, and a significantly reduced cost and timeline to clinical availability.(10,11)
Actually, drug repositioning is not a new strategy; many drugs have been successfully repositioned, including zidovudine (1, cancer → HIV), gemcitabine (2, viral infections → cancer), sildenafil (3, heart related chest pain → erectile dysfunction), amphotericin B (4, leishmaniasis → fungal infections), bromocriptine (5, Parkinson’s disease → type 2 diabetes), finasteride (6, enlarged prostate → scalp hair loss), methotrexate (7, chemotherapy agent → immune system suppressant), minoxidil (8, antihypertensive vasodilator medication → androgenic alopecia), ketoconazole (9, fungal infections → Cushing’s syndrome), fingolimod (10, immunomodulating drug → multiple sclerosis), raloxifene (11, osteoporosis → breast cancer), and thalidomide (12, antiemetic drug → multiple myeloma) (Figure 2).(12,13)
Figure 2
Figure 2. Examples of drugs that have been repositioned: finding and developing new uses for the approved drugs.
Additional successful examples of drug repositioning have been reported. For example, in 2017, levosimendan (13, used to treat heart failure) was identified through screening of an FDA-approved drug library as a novel and promising HIV-1 inhibitor targeting viral transcription. Levosimendan displayed robust potency against TNFα-induced HIV-1 reactivation in many cell lines with HIV-1 latency via the HIV-1 Tat-LTR transcriptional axis. Moreover, it inhibited not only acute viral replication but also the reactivation of latent HIV-1 proviruses in primary CD4+ T cells.(14)
In recent years, many chemically diverse FDA-approved drugs with potency for inhibiting the cell entry of Ebola virus have been identified; these include benztropine (14), bepridil (15), paroxetine (16), sertraline (17), toremifene (18), imipramine (19), clomipramine (20), and thioridazine (21), which directly bind with Ebolavirus glycoprotein.(15)
In 2018, pharmacological inhibition of neuraminidase by two anti-influenza agents, oseltamivir (22) and zanamivir (23), was found to protect cardiomyocytes and the heart from myocardial injury. Subsequently, a key role of Neu5Ac in acute myocardial infarction was confirmed by functional metabolomics studies, and neuraminidase-1 was identified as a previously unrecognized therapeutic target for coronary artery diseases.(16)
In 2018, through screen of a fragment library (2500 compounds), Urquiza et al. identified the antifungal ciclopirox as a binder to and stabilizer of uroporphyrinogen III synthase, a drug target of congenital erythropoietic porphyria (CEP), thereby restoring activity of the enzyme. Also, ciclopirox exhibits orally effective in vivo activity and low toxicity, in a genetic mouse model of CEP.(17)
In 2019, via cell-based reporter assays, primary cell culture, and multiple mouse models, it was found that non-nucleoside HIV-1 reverse transcriptase inhibitor efavirenz is a potent pregnane X receptor (PXR)-selective agonist that can efficiently activate PXR to induce hypercholesterolemia and hepatic steatosis.(18)
Via screening 2486 FDA-approved drugs, new Na+/K+ ATPase inhibitors were identified, which enable the dissociation of circulating tumor cells clusters into single cells, resulting in DNA methylation remodeling at critical regions and metastasis suppression.(19)
In 2019, it was reported that three salicylanilide anthelmintic drugs, namely, niclosanide (24), oxyclozanide (25), and rafoxanide (26), showed significant antiadenovirus potency at low micromolar concentrations with little cytotoxicity. Furthermore, the mechanistic assays show differences in the way the drugs exert antiadenovirus potency. Compounds 24 and 26 target transport of the human adenovirus type (HAdV) particle from the endosome to the nuclear envelope, while 25 specifically targets the early gene E1A transcription step of adenovirus.(20)
1.1. New Developments on Drug Repurposing
Today, most strategies for repositioning are based on phenotypic screening and systematic screening (robotic high-throughput screening, HTS) using a panel of approved drugs.(21,22)
Identifying the molecular targets of compounds from phenotypic screening is a challenging but crucial step toward understanding their mechanisms of action. In this context, many target identification methods have been used to successfully elucidate the target proteins of a variety of compounds. For example, chemoproteomics has proven an effective tool to identify protein targets from phenotypic assay and to understand on- and off-target engagement of potential bioactive agents. Mass spectrometry (MS)-based proteomics is the primary technology for target identification.(23) Moreover, photochemistry (live-cell photoaffinity labeling) has been employed recently to identify novel targets for known molecules.(24−26)
In recent years, with the continuous development of bioinformatics and cheminformatics, drug repurposing has gradually developed into a data-driven innovative drug development strategy. Recent work has demonstrated that bioinformatics-based methodologies have the potential to provide the kind of systematic insights into the complicated relationships among diseases, targets, and drugs that are needed for successful repositioning.(27,28)
With the guidance of bioinformatics and cheminformatics, recent progress has also been made in exploration of the chemical space of existing drugs for novel bioactivities with translational potential (Figure 3). For example, zileuton (27, trade name ZYFLO) is an orally bioavailable inhibitor of 5-lipoxygenase and thus inhibits formation of leukotrienes (LTB4, LTC4, LTD4, and LTE4); it is used for the treatment of asthma. Based on previous studies indicating that the leukotriene pathway is involved in human tauopathy (bioinformatics), it was recently shown that aged tau transgenic mice treated with zileuton exhibit reversal of learning impairments, memory deficits, and neuropathology.(29)
Figure 3
Figure 3. Identifying and developing new uses from existing (investigational) drugs via new approaches or further optimization.
Suberanilohydroxamic acid (SAHA, vorinostat, 28), an approved histone deacetylase (HDAC) inhibitor, was used for treating cutaneous T cell lymphoma. Previous studies suggested that 28 showed potential anti-inflammatory activity (cheminformatics), though the underlying mechanisms remained unclear. Based on this, Lu et al. reported drug repurposing of HDAC inhibitors as agents to alleviate neutrophilic inflammation in idiopathic pulmonary fibrosis and acute lung injury via binding with leukotriene A4 hydrolase, thereby inhibiting leukotriene B4 biosynthesis.(30)
Integrating computational prediction and experimental validation has great potential to improve the success of drug repositioning.(31,32) In 2014, Huang et al. reported a combination of systems biology and multiple microarray experimental approaches to find and characterize the function of novel oncogenes associated with hepatocellular carcinoma and lung cancer. This was helpful in drug repositioning discovery.(33)
A plethora of in silico approaches have been developed to facilitate the repositioning of drug-like molecules, including virtual screening, reverse pharmacophore profiling, or binding pocket comparisons. For example, NorA is the most important efflux pump of Staphylococcus aureus as it confers multidrug resistance. Astolfi et al. constructed a ligand-based 3D-pharmacophore model of efflux pump inhibitors (EPIs) based on the S. aureus (ModB and ModC) NorA EPIs library. The best model was screened against approved drugs, leading to the discovery of novel and potent NorA EPIs, including three nonantibiotic approved drugs dasatinib (29, used to treat certain cases of chronic myelogenous leukemia and acute lymphoblastic leukemia), gefitinib (30, used for certain breast, lung, and other cancers), and nicardipine (31, used to treat high blood pressure and angina) that were able to restore the antibacterial activity of ciprofloxacin against resistant S. aureus strains overexpressing NorA.(34)
Using a computational screen of an FDA-approved drug library, the proton pump inhibitor lansoprazole (32) was repositioned as an anticancer drug by binding to the thioesterase domain of human fatty acid synthase.(35)
Multiple ligand simultaneous docking (MLSD) is a computational tool used to investigate interactions between a biotarget and substrate in the presence of an inhibitor. In 2011, Li et al. described a novel approach to drug discovery by combining fragment-based drug design with drug repositioning using MLSD. This led to the identification of celecoxib and its analogues as new inhibitors of signal transducer and activator of transcription 3 (STAT3).(36a) In 2014, they further reported the identification of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 protein–protein interaction through MLSD-derived drug-repositioning methodology.(36b) Novel in silico drug design approaches, especially those related to machine-learning algorithms, are being utilized for in silico drug repositioning, as exemplified by drug profile matching,(37) topological graph theory,(38) and other computational methodologies.(39−41)
Because of the limited variety of drugs on the market, it is necessary to expand the selection of drugs or drug-like molecules (investigational compounds). As we know, development of repurposed drugs is also limited by challenges in the regulatory path.(42) Widening the scope of compound library beyond approved drugs can help overcome this shortcoming.
For example, three pyrimidinone derivatives 33a–c, previously known as nonapproved HIV-1 non-nucleoside reverse transcriptase inhibitors, were reported to inhibit cell proliferation and facilitate cell differentiation via inhibiting (a nontelomeric) endogenous reverse transcriptase.(43)
Robotic HTS of a natural compound library (Spectrum), a library of pharmacologically active compound (LOPAC), and an FDA-approved drug library (Prestwick) against Plasmodium falciparum Hsp90 (PfHsp90) resulted in three hits: (±)-2-amino-3-phosphonopropionic acid (34) (APPA) from LOPAC and harmine (harmaline) (35) and acrisorcin (36, a combination of the active ingredients 9-aminoacridine and 4-hexylresorcinol) from Spectrum. These compounds were identified as selective PfHsp90 inhibitors, with IC50 values in the nanomolar level in a cell-based antimalarial assay, and showed synergistic potency in the presence of chloroquine, a drug used to prevent and to treat malaria.(44)
Selective optimization of off-target activities represents an original alternative to HTS. For example, the 1,2,4-triazol-3-ylthioacetanilide RDEA806 (37) was once advanced into phase IIa clinical trials as a promising novel anti-HIV-1 drug candidate in Ardea Biosciences (a subsidiary of AstraZeneca). Meanwhile, it also showed uric acid lowering potency and potential for the chronic management of hyperuricemia and gout. In a follow-up study, 1,2,4-triazol-3-ylthioacetic acid RDEA594 (38), a major metabolite of RDEA806 was identified, which retained all the uric acid lowering effects of RDEA806, but no antiviral potency. Compound 38 is an orally bioavailable inhibitor of urate-anion exchanger transporter 1. In December 2015, 38 was approved by the FDA, named Lesinurad, ZURAMPIC as combination therapy with a xanthine oxidase inhibitor for treating hyperuricaemia and gout.(45,46)
Depending on the new indication, the repurposed (experimental) drugs may need further medicinal chemistry optimization to improve their potency and selectivity as potential clinical candidates for clinical therapy. For example, Itraconazole (ITZ, 39) is a clinically efficacious antifungal agent. Recent drug-repurposing projects identified ITZ as a potent anticancer agent through its off-target activity, including the vascular endothelial growth receptor 2 (VEGFR2), mTOR signaling and hedgehog (Hh) signaling pathways. To fully investigate the structural requirements for these anticancer properties, various ITZ derivatives were prepared and evaluated for anti-Hh and antiangiogenic activities (exemplified by 40a). The results suggest that the triazole functionality is indispensable to ITZ-mediated inhibition of angiogenesis, but that it is not required for inhibition of Hh signaling.(47) Further optimization suggested that modification of the sec-butyl side chain of ITZ can result in improvement of the pharmacological activity (HUVEC proliferation or VEGFR2 glycosylation) of itraconazole.(48a) In an effort to eliminate ITZ’s inhibition of CYP3A4 (the drug metabolizing enzyme) while retaining antiangiogenic activity, a series of derivatives were designed and prepared in which the 1,2,4-triazole ring was replaced with a set of azoles and other rings. Among these analogues, 40b with tetrazole in place of 1,2,4-triazole displayed the best effect on HUVEC proliferation with an IC50 of 73 nM with extremely weak inhibition of CYP3A4 (EC50 > 20 μM). Similar to itraconazole, 40b could induce Nieman-Pick C phenotype and inhibit AMPK/mTOR signaling.(48b)
Pretomanid (41, PA-824) is an experimental antituberculosis drug. Phenotypic screening of pretomanid derivatives toward kinetoplastid diseases unexpectedly resulted in the discovery of DNDI-VL-2098 (42) as a promising first-in-class drug candidate for visceral leishmaniasis. Additional SAR studies led to the discovery of phenylpyridine derivatives (43, 44) with significantly improved potency in a mouse model of acute Leishmania donovani infection.(49)
Tozasertib (45) was originally developed as an anticancer agent targeting AurA. One iteration of automated multiobjective in silico design (computational chemistry and machine learning) was sufficient to shift the selectivity of tozasertib toward the pain target TrkA. Compound 46 was selected as a top-ranked molecule from a focused library derived from tozasertib, which showed 10,000-fold improved selectivity versus AurA, cellular activity at nanomolar concentration, and high selectivity for TrkA versus a kinase panel.(50)
A HTS approach identified the antihistamine terfenadine (47) as possessing previously unreported antimicrobial potency against Staphylococcus aureus (S. aureus) and other Gram-positive bacteria. Mechanism of action investigations by Perlmutter et al. indicated that terfenadine-based analogues (exemplified by 48) displayed antibacterial potency, at least in part, through inhibition of bacterial type II topoisomerases.(51)
The nucleoprotein (NP) of influenza A virus is a promising target for new antivirals. Previously, naproxen (49) was disclosed as a dual inhibitor of NP and cyclooxygenase cyclooxygenase-2 (COX2), with antiviral and anti-inflammatory potency by in silico screening. Very recently, further optimization using traditional medicinal chemistry strategies to remove COX2 inhibition potency afforded derivatives 50a and 50b with improved antiviral potency in infected cells, without inhibiting COX2. This improved antiviral potency probably results from these two derivatives inhibiting the interactions between NP and RNA and polymerase acidic subunit N-terminal, respectively.(52)
Biology-oriented drug synthesis has great potential to explore compounds derived from commercial pharmaceutical drugs for new and diversified biological potential by adopting simple chemical transformations.(53)
Overall, drug repurposing, combined with innovative methods for drug validation, has greatly contributed in recent years to the discovery of novel antiviral molecules, broad-spectrum antiviral agents (BSAA), and targets for therapeutic intervention.(54)
In particular, the discovery and development of BSAA has been a key aim of antiviral research,(55) and various broad-spectrum nucleoside derivatives, host-targeting antiviral agents, and immune-modulating agents have been reported (Figure 4). For example, ribavirin (51), a nucleoside analogue with broad-spectrum antiviral potency, is effective against a mammalian bornavirus, avian bornaviruses, and Borna disease virus.(55) Sofosbuvir (52), a clinically approved anti-HCV drug, also inhibits Zika virus RNA polymerase.(56) Favipiravir (53, T-705), a broad-spectrum antiviral compound approved in Japan for treating influenza virus infection, has already been used off-label to treat patients infected with Ebola virus and Lassa virus.(57) Nitazoxanide (54), a FDA-licensed drug for treatment of enteritis due to protozoa, parasites, and anaerobic bacteria, also displays a variety of antiviral potencies and is currently in phase II/III clinical trials for treatment of infections caused by influenza viruses, HCV, norovirus, and rotavirus.(58)
Figure 4
Figure 4. Representative broad-spectrum antiviral drugs.
Host-based antiviral agents could interfere with viral pathogenesis by targeting host cellular factors required for viral infections or innate immune responses.(59) Several potent inhibitors of inosine-5′-monophosphate dehydrogenase(60−63) and inhibitors of phosphatidylinositol 4-kinase IIIβ(64) have in vitro antiviral potency against a range of DNA and RNA viruses (HCV, human rhinovirus, and coxsackievirus B3, Zika virus, norovirus, influenza virus, and dengue virus). Recently, it was reported that ITZ also displayed broad-spectrum antiviral potency against enteroviruses, cardioviruses, and HCV, via targeting oxysterol-binding protein, a cellular lipid shuttling machinery. The core structure bearing five rings and the sec-butyl chain are crucial to antiviral potency, whereas the triazole ring, which is indispensable to antifungal potency, is not.(65)
1.2. “Privileged Structure” Repositioning
The hit rates by repositioning of commercially available approved or experimental drug libraries are usually quite low, and the hits often have low structural diversity. As a supplement, compound collections based on privileged structures offer the potential of libraries encompassing favorable physicochemical profiles and containing privileged scaffolds known to target various cellular targets, thereby increasing the success rate of discovering selective molecules that inhibit specific targets. In this section, it is intended to be illustrative rather than comprehensive, and the examples are chosen to convey the range of opportunities available and the current state of the art of “privileged structure” repositioning, highlighting its contributions to new drug discovery.
1.2.1. Diversity-Oriented “Privileged Structure” Repositioning
Diversity-oriented synthesis (DOS) based on privileged structures employed in existing drugs frequently have other, undiscovered activities. This observation highlights opportunities for drug discovery through screening of drug (lead)-like compound libraries; the resulting hits are likely to be safer and less expensive to develop than conventional hits, as well as having a shorter development timeline.(66,67)
1,6-Naphthyridine-7-carboxamide (in pink) has been regarded as a promising motif with drug-like properties. Among structurally diverse HIV-1 integrase inhibitors, the 8-hydroxy[1,6]naphthyridine L-870,810 (55) was a promising anti-HIV drug candidate, but in spite of its pharmacological activity, the development of 55 was halted during phase I clinical studies (reasons unknown). Nevertheless, because of its desirable drug-like properties, novel derivatives of 55 (substitutions at the 5- and 8-positions) were designed to overcome the limitations of naphthyridine-7-carboxamides as antiviral compounds and to reposition them as novel cytotoxic anticancer agents. Finally, further structural decoration of the 5,8-disubstituted-[1,6]naphthyridines (on 7-carboxamide) afforded novel molecules 56a–c with remarkable cytotoxicity toward a set of cancer cell lines and high potency against selected oncogenic kinases (Figure 5).(68)
Figure 5
Figure 5. Discovery of bioactive molecules via diversity-oriented “privileged structure” repositioning approach.
In addition, a newly synthesized tractable tricyclic scaffold has been incorporated into new analogues of bioactive drug candidates across multiple target families, affording the potent serine peptidase DPP-4 inhibitor 57, a CCR5 receptor antagonist 58, and the highly selective PI3K δ isoform inhibitor 59.(69) Overall, the platform described in this section is widely applicable to accelerate drug discovery by using privileged structures from drugs approved for other indications.
1.2.2. Target Similarity-Inspired “Privileged Structure” Repositioning
Taking into account the structural understanding of targets, the design and screening of focused libraries (target-oriented synthesis, TOS) based on privileged structure platforms provide an efficient strategy to explore chemical space and to discover novel hits. For example, α-carboxynucleoside phosphonate (α-CNP) 60 with a cyclopentyl linker between the nucleobase and α-carboxyphosphonate inhibits HIV-1 reverse transcriptase preferentially (50 to 100 fold) over herpetic DNA polymerases. Interestingly, modifications in the linker moiety (compound 61) resulted in pronounced shift of the inhibition target (∼50 to 100 fold) from HIV reverse transcriptase to herpetic DNA polymerases (Figure 6).(70)
Figure 6
Figure 6. Discovery of bioactive molecules via target similarity-inspired “privileged structure” repositioning.
Ribonuclease H (RNase H)-like superfamily, also called retroviral integrase superfamily (including some metalloenzymes: HIV integrase, HIV RNase H, HBV RNase H, human cytomegalovirus pUL89 endonuclease, the NS1 protein of parvovirus B19, influenza virus polymerase acidic endonuclease), has attracted great attention as a potential drug target. The metalloenzyme activity is dependent on metal ions located in the catalytic site.(71) The shared enzymatic mechanism employed by many dication-dependent polynucleotide metabolizing enzymes provides a huge opportunity for a multipronged drug discovery effort. Divalent metal ion chelators, such as N-hydroxyimide, diketo acid, α-hydroxytropolone, pyrimidinol carboxylic acid chemotypes, etc., were reported as broad-spectrum antiviral agents via chelation of active-site divalent metal ions of metalloenzymes (as exemplified by 62 and 63).(72−74) For example, some anti-HIV RNase H compounds can inhibit HIV integrase, and vice versa.(72,74) Compounds prepared during anti-HIV RNase H screening should be screened against HBV; moreover, toxicity data of some of these molecules is known.(72) The endonuclease domain (pUL89-C) has an ribonuclease H/integrase-like fold. Like ribonuclease H, pUL89-C endonuclease function is dependent on metal ions in the catalytic site. pUL89-C endonuclease function was inhibited by HIV integrase inhibitor raltegravir.(73e)
Baloxavir marboxil (66, trade name Xofluza) is a cap-dependent endonuclease inhibitor for treatment of influenza A and influenza B, FDA-approved in October 2018 and given via oral single dose once/day. It shares a similar metal-chelating pharmacophore (red) in the structures of HIV integrase inhibitors dolutegravir (64) and bictegravir (65), which was prepared from readily derivatizable building blocks with well-established preparation methods.(75)
Analogously, based on integrase inhibitor-like pharmacophore (N-alkyl-5-hydroxypyrimidinone carboxamide in Raltegravir (67)), target similarity-inspired “privileged structure” repositioning resulted in the discovery of N-alkyl-5-hydroxypyrimidinone carboxamide 68 as a novel antitubercular agent against Mycobacterium tuberculosis.(76)
2. Bioorthogonal Chemistry-Inspired Drug Discovery
ARTICLE SECTIONS
Bioorthogonal chemistry, referring to the chemical reaction that can occur at physiological conditions without interference from biomolecules, has been widely used in chemical biology and gradually used in drug discovery.(77) Several chemical reactions have been developed that fulfill the criteria of bioorthogonality, as exemplified by commonly used Cu(I)-catalyzed or strain-promoted azide–alkyne cycloaddition, Staudinger ligation, or the 1,3-dipolar cycloaddition between cyclooctynes and nitrones, thiol–ene click chemistry, and oxime/hydrazone formation from ketones and aldehydes, which have greatly facilitated the hit identification.
2.1. Rapid Assembly and Screening of Focused Combinatorial Fragment Libraries
In current drug discovery, parallel HTS or phenotypic screening of large compound collections is considered an effective approach to exploit chemical space and rapidly find hit compounds. However, the time-consuming and labor-intensive compound separation processes prior to evaluation have been bottlenecks in drug discovery.(78) In recent years, the rapid assembly and direct screening of focused combinatorial fragment collections in microtiter plates (or in parallel reactors) using bioorthogonal reaction (predominantly, click chemistry) has been developed as a robust and efficient method to establish structure–activity relationships (SARs) and for discovering bioactive molecules (Figure 7),(79) as exemplified by the discovery of HIV-1 PR inhibitors 69–71,(80) highly selective and potent epigenetic inhibitors 72–76 (HDACs and SIRTs),(81) JAK inhibitor 77,(82) and glucocerebrosidase inhibitor 78.(83) In our recent review, the inherent limitations and challenges facing this methodology were critically discussed.(79)
Figure 7
Figure 7. Discovery of highly potent and selective inhibitors through click chemistry-based combinatorial fragment assembly. CuAAC: copper(I)-catalyzed azide–alkyne [3 + 2] dipolar cycloaddition.
Undoubtedly, the success rate of this fragment-based drug discovery methodology relies on the information on detailed binding conformation and binding affinity of a range of small fragments bind to their respective targets. Besides, exploration of other HTS-amenable organic reactions suitable for efficient synthesis and screening of diverse chemical libraries, such as copper-free click chemistry, is crucial in overcoming these problems.(84−86)
2.2. Target-Guided Synthesis (TGS) Approaches
Target-guided synthesis (TGS) has proven a robust strategy in recent years for its original concept: using the biological target itself to assemble its selective ligands directly from a pool of fragments bearing complementary reactive functional groups. The approaches, bridging the gap between chemical synthesis and bioactivity assays, are divided into two major approaches: the kinetic TGS (KTGS) approach (Figure 8A), namely, the kinetically controlled reactions involving irreversible bond formation,(87) and the thermodynamically controlled reactions involving reversible reactions (also known as dynamic combinatorial chemistry, DCC) (Figure 8B).(88) Both strategies have been extensively and successfully implemented for hit finding for receptors and enzymes,(89) such as neuraminidase,(90) carbonic anhydrase,(91) kinase/phosphatase,(92) cyclooxygenase-2,(93) etc.
Figure 8
Figure 8. (A) KTGS principle. Best building blocks from each binding pocket of the biomolecule would preferentially react together because of their spatial proximity and afford the corresponding dimeric binder displaying synergistic bioactivity. (B) Thermodynamically controlled TGS or DCC principle. From appropriate fragments under equilibrium conditions, suitable dynamic combinatorial libraries (DCLs) are built up, allowing the generation of all possible library members in a thermodynamically controlled distribution (via selection pressure of the biotarget).
Particularly, structure-guided fragment linking of precursors that display weak affinity to the target (the KTGS approach) is considered a robust way to rapidly find potent inhibitors, based on cooperative binding. In KTGS approach, the biotarget accelerates the irreversible reaction (in situ click chemistry) between complementary fragments by bringing them into close proximity in proper orientation.(89) In 2017, Wang et al.(94) reported two cell-permeable O-GlcNAc transferase (OGT) inhibitors (79 and 80, IC50 = 139 and 66.7 μM, respectively), developed from low-activity components (IC50 > 1 mM) via a kind of dynamic combinatorial chemistry, namely, “tethering in situ click chemistry” (Figure 9A). The discovery of these compounds supports the idea that tethering in situ click chemistry can be utilized to search novel lead molecules from weak-binding fragments.(94)
Figure 9
Figure 9. Kinetic target-guided synthesis of (A) cell-permeable O-GlcNAc transferase inhibitors and (B) Bcl-X(L)/BH3 protein–protein interaction modulators.
In 2011, Manetsch et al. reported the use and validation of KTGS via the sulfo-click reaction between sulfonyl azides and thio acids as a valuable tool for the discovery of potent modulators targeting protein–protein interaction (as exemplified by Bcl-X(L)/BH3), acylsulfonamides 81–84 (Figure 9B).(95,96) These results demonstrated that KTGS based on the sulfo-click reaction is a screening and synthesis platform for the straightforward identification of high-quality modulators.(96)
However, in most cases, target-guided synthesis requires purified proteins, which limits its application. In 2018, by applying metabolomics methods, Antti et al. demonstrated that target-guided synthesis with target proteins can also be achieved directly in cellular environments.(97) This method opens up new possibilities to screen drug candidates for difficult target proteins in cell-based systems.
Recently, the tetrazine bioorthogonal reaction has been used by Astex Pharmaceutical to stitch together functional proteolysis targeting chimeras (PROTACs) for degrading anticancer drug targets BRD4 and ERK1/2 within living cells (Figure 10). Notably, in situ assembly of two small compounds within a cell demonstrated higher efficacy than simply adding the preassembled compound.(98)
Figure 10
Figure 10. Tetrazine bioorthogonal reaction was used to form drug-like heterobifunctional molecule 87 inside cells, as the BRD4 degrader via the ubiquitin pathway.(98)
However, DCC represents a promising approach for a highly efficient generation of libraries.(89) As yet, however, this approach is limited by the techniques used for the analysis of protein–binder complexes and the few appropriate reactions. Several techniques have been used to the analysis of protein-directed DCL. These include X-ray crystallography, NMR spectroscopy, HPLC, and mass spectrometry. X-ray crystallography and NMR spectroscopy are high-resolution techniques, but are time-consuming. Notably, competitive MS binding assays have proved to be an effective method for the affinity determination of single molecule toward a protein of interest, which has been readily extended to the screening of compound collections as well. In the search of new γ-aminobutyric acid transporter 1 (GAT1) inhibitors, an exploratory research was undertaken in which pseudostatic hydrazone libraries were generated by DCC and screened against GAT1 using MS binding assays (Figure 11). Hydrazone 88 bearing a 2′,4′-dichlorobiphenyl moiety was identified as a robust binder with low nanomolar affinity (pKi = 8.1). Further optimization afforded 89 (pKi = 6.9) as a stable carba analogue of hydrazone.(99)
Figure 11
Figure 11. GAT1 inhibitor hits 88 and 89 were obtained by means of library screening and further optimization.
Besides, the efficient dynamic-combinatorial MS technique has the advantages of providing detailed information on mass shifts. In recent years, the disulfide or boronic acid/boronate ester dynamic systems coupled with protein MS analysis has been employed in the rapid discovery of JmjC histone demethylases and nucleic acid demethylases.(100)
To expand the potential and scope of DCC, very recently, a novel multiprotein DCC strategy was developed, which combines the sensitivity of differential scanning fluorimetry and the discriminatory power of a zwitterionic “thermal-tag”. This methodology enables simultaneous identification of subfamily selective inhibitors against several targets of interest.(101) It was illustrated that from aldehyde and amine fragments a quadruplex nanotemplate can dynamically select and amplify selective G quadruplex DNA binders, which further enriched the literature in this area and indicate the increasing level of interest in this field.(102)
2.3. Bioorthogonally Activated Chemotherapy (Bioorthogonal Uncaging Strategies)
Complementary to bioorthogonal reactions that ligate two molecules, there is an increasing interest in reactions that cleave a linker or release a molecule. Such dissociative bioorthogonal reactions have a broad spectrum of uses, including in drug delivery.(103)
To avoid toxic side effects on healthy cells and tissues, much research has been directed at the design of cancer-specific strategies (selective delivery of chemotherapeutic drugs to cancer cells), for example, by using prodrugs via controlled activation, which are inactive precursors of cytotoxic agents, but can be biochemically converted into their active forms in a spatially controlled manner. Recent advances in bioorthogonal catalysis are increasing the ability of medicinal chemists to manipulate the fate of molecules in complex biological systems. Consequently, bioorthogonal uncaging (bioorthogonally activated chemotherapy, also termed “click to release”) have been recently reported as an experimental prodrug therapeutic strategy to control drug release by the application of solid metals (mainly palladium) as implantable activating devices to catalyze various chemical reactions in biocompatible environments and to modulate the cytotoxicity of anticancer agents in specific biological settings.(104,105) While soluble palladium species such as Pd2+ complexes exert inherent cytotoxicity, Pd(0) catalysts are biocompatible and seem to be the safer agents.(105)
Recently, Unciti-Broceta reported palladium-labile biorthogonal prodrugs (92–95) of several anticancer drugs, including cytotoxic gemcitabine (2),(105d) 5-fluorouracil (90, 5FU),(105e,f) floxuridine (91),(105g) and vorinostat (28)(105h) by introducing a Pd(0)-cleavable group (N-propargyloxycarbonyl (N-Poc) promoiety) at positions that are mechanistically relevant for the bioactivity of the original anticancer agents. As shown in Figure 12, such prodrugs are converted into cytotoxic agents selectively in the presence of Pd(0). For example, a Pd(0)-functionalized device could be surgically implanted in the affected area of tissue or organ, enabling local treatment of the disease with prodrugs, while reducing side effects in distant tissues and organs.(105) Very recently, new Pd-labile NO precursors were reported, which can be effectively uncaged by a biocompatible Pd(0) catalyst via bioorthogonal bond cleavage to release NO in living cancer cells, eliciting a potent antiproliferative effect.(106)
Figure 12
Figure 12. Bioorthogonally activated palladium-labile prodrug strategy and toxigenic mode of action (Prototype drugs were highlighted in blue).
There remains great interest in novel bioorthogonal uncaging strategies, as exemplified by the newly disclosed inverse electron-demand Diels–Alder reaction and gold-triggered uncaging chemistry.(107,108)
Another prominent example is the application of the highly strained alkene transcyclooctene and ene ether to mask functional groups, including amines and alcohols (Figure 13), which is then liberated upon reaction with a tetrazine.(109) In 2018, the group of Wang reported a concentration-sensitive bioorthogonal prodrug activation approach by taking advantage of reaction kinetics-controlled tetrazine–cyclooctyne click reaction, and spontaneous cyclization-based release. This study robustly demonstrated the concept of enrichment-triggered prodrug activation specifically in mitochondria and the critical feasibility of treating the related clinical diseases such as cancer and acute liver injury.(110)
Figure 13
Figure 13. Schematic illustration of the application of the highly strained alkene transcyclooctene and ene ether to mask an amine or alcohol.(109)
In summary, the use of bioorthogonal reactions to trigger caged groups furnishes a great opportunity to activate on the human body and could be translatable to patients in theory. We anticipate that more and more investigators will apply “click to release” approaches to trigger the release of drugs in vitro and in vivo.(110b)
3. Photoactivatable Medicinal Chemistry
ARTICLE SECTIONS
Light has been used to suddenly liberate a ligand or substrate by removing a photolabile-protecting group (PPG) from a suitable precursor molecule to produce reactive oxygen species from photosensitizers or to control the activity of ligands in precise spatiotemporal manner to investigate the structure and function of important biotargets, and different concepts may be followed, as exemplified by photoactivatable caged (phototriggering) prodrug, photodynamic therapy, and photoswitchable ligands. These are collectively referred to as “photoactivatable medicinal chemistry”.
3.1. Photoactivatable Caged Prodrug
A newly emerging approach to regulate the action of bioactive compounds in a spatial and temporal control manner employs PPGs.(111) The PPG is a chromophore covalently linked to the pharmacophoric group of the bioactive compound, thus inhibiting its bioactivity, a concept known as “caging” (the photo prodrug). The covalent bond between the PPG and the drug molecule is broken by irradiation with ultraviolet light, resulting in the formation of the parent drug molecule (“uncaging”).
The off-target effects of systemically administered anticancer drugs heavily constrained their efficacy and tolerability. The photocaging concept has been used in the delivery of drugs across membranes; it reduces off-target effects, as exemplified by photoactivatable prodrug (97) of the antimelanoma agent vemurafenib (96),(112) caged RET kinase inhibitor 99,(113) photoactivatable caged prodrugs (101 and 102) of imatinib (100),(114) photocontrolled HDAC inhibitors 103, 104,(115,116) and 106, a photoactivatable prodrug of doxazolidine (105) targeting exosomes (Figure 14).(117)
Figure 14
Figure 14. Photoactivatable caged kinase inhibitors, HDAC inhibitors, and photoactivatable prodrug of doxazolidine targeting exosomes. Essentially, the photo prodrug concept is based on the mask of a pharmacophoric moiety. The PPG (pink) is therefore attached to the bioactive compound by a covalent bond. The parent bioactive molecules can be released by irradiation with ultraviolet light. Therefore, this method might improve higher drug concentrations in the area of interest sparing other compartments (such as cancer-afflicted tissues) in a rapid and efficient manner with lower side effects.
Meanwhile, a number of PPGs have been exploited for this purpose, including p-nitrobenzyl, 4,5-dimethoxy-2-nitrobenzyl, 7-diethylaminocoumarin-4-ylmethyl, and 6-bromo-7-hydroxycoumarine-4-ylmethyl. The successful application of the photoactivation concept to some kinase inhibitors and HDAC inhibitors afforded further evidence for this concept as a feasible approach in many other fields.(118,119) These photoactivatable caged prodrugs can be useful as pharmacological probes to investigate the impact of the parent molecules toward biological systems.
3.2. Photodynamic Therapy
Photodynamic therapy (PDT) is well studied and established in clinical application since the approval of the first drug, porfimer sodium, based on the characteristics of strong metabolism of tumor cells, after injection of photosensitizers (drugs), the concentration of tumor tissue is notably higher than that of neighboring normal tissues. At appropriate time, light irradiation with specific wavelength could activate photosensitizers, produce reactive oxygen species (such as singlet oxygen), and specifically kill cancer cells and destroy neovascularization.(120) PDT has proven a promising treatment option for various kinds of cancers and nonmalignant diseases including infections. Even though several photosensitizers have been clinically approved already, the development of additional photosensitizer with high phototoxicity, low dark-toxicity, and favorable aqueous solubility is very challenging for PDT.(121−123)
Several methods have been employed to obtain more efficient and less toxic photosensitizers. For example, conjugation with tumor-specific ligands (including small molecules, peptides, and proteins) significantly improves the selectivity of the active photosensitizer toward specific cells. In 2017, the conjugates 107 and 108 were synthesized by coupling zinc phthalocyanine to gonadotropin-releasing hormone (GnRH) analogues. Compared to unmodified zinc phthalocyanine, conjugates 107 and 108 demonstrated higher and more specific phototoxicities against breast cancer cells and robust in vivo anticancer efficacies (in animal model). Conjugate 108 exhibited a high safety profile for its low retention in brain and skin (Figure 15).(124)
Figure 15
Figure 15. Photosensitizers 107 and 108 mediated by GnRH receptors, and 109, the far-red light-activatable prodrug of PTX.
In 2016, compound 109, the far-red light-activatable prodrug of paclitaxel (PTX), was prepared by conjugating the photosensitizer via singlet oxygen-cleavable aminoacrylate linker (Figure 15). Through the combined effects of site-specific paclitaxel chemotherapy and photodynamic therapy, the cytotoxicity was significantly reduced.(125)
A recent study shows that hydroxypyridinone and 5-aminolaevulinic acid conjugates could substantially enhance the formation of phototherapeutic metabolite and phototoxicity.(126) In 2018, a novel series of porphyrin-based water-soluble derivatives were reported as potential sensitizers for effective PDT against breast cancer.(127) In 2018, two advanced boron dipyrromethene (BODIPY)-based photosensitizers with a glibenclamide-derived moiety were reported to behave as singlet oxygen provider with high photostability.(128)
This direction will continue to be a hot topic in the field of anticancer drugs.(129) In the future, it would be of high interest to explore if the photodynamic effectiveness may be improved and, at the same time, if the systemic toxicity may be reduced by photosensitizers that circulate in their inactive form in the normal tissues and are activated only by specific conditions in cancer cells (e.g., lower pH value, reducing environment). Furthermore, research in this direction should pay attention to questions like: a high concentration of glutathione present in the tumor tissues can consume reactive oxygen species; PDT is often followed by recurrence because of incomplete ablation of tumors.
3.3. Photoswitchable Ligands: Azobenzenes
There is growing interest in designing spatiotemporal control over enzyme activities using noninvasive stimuli, as exemplified by light.(130) Photoswitchable ligands, also termed photochromic ligands, are a class of molecules whose activity at a target of interest can be controlled precisely in a reversible manner by light. When irradiated with light of a certain wavelength, such molecules undergo a configurational change in their structure in a reversible way, which may substantially alter their binding affinity to a specific target.(131)
In recent years, azobenzenes were used as photoswitch due to favorable geometric and photochemical properties. This approach resulted in discovery of potent photoswitchable inhibitors (110 and 111) of γ-aminobutyric acid transporter,(132) a potent photochromic antagonist 112 that selectively targets the calcium ion permeable AMPA-type of ionotropic glutamate receptors,(133) and phototrexate (114), a photochromic analogue of methotrexate (113) as the human dihydrofolate reductase inhibitor (Figure 16).(134) All in all, this design approach opens new avenues for optically controlling enzyme function and optochemical biology.(135)
Figure 16
Figure 16. Chemical structures of phototrexate in the trans (in the dark and under blue/white light illumination) and cis (under UVA illumination) configurations.
4. Lead Diversification via Late-Stage Functionalization
ARTICLE SECTIONS
Several strategies have been employed to generate collections of compounds with complex scaffolds, including diversity-oriented synthesis (DOS).(136) The direct functionalization of complex scaffolds at a late stage, namely, late-stage functionalization (LSF), is another often used approach to build derivatives efficiently with precise and substantial modifications to the platforms of these molecules without resorting to de novo synthesis.(137) In recent years, there is a lot of research on LSF, which has enabled rapid diversification of drug-like molecules or drug candidates to improve their potency and drug-likeness. Many innovative methods have been developed for this endeavor, including late stage C–H functionalization, nucleophilic aromatic substitution, etc.
C–H activation reactions are valuable tools for medicinal chemists to directly introduce functional groups into a bioactive compound at a late stage of synthesis.(138) For example, in the optimization of NCH-31 (115), a histone deacetylase (HDAC) inhibitor, a late-stage C–H coupling approach enabled rapid identification of novel derivatives IYS-10 (116a) and IYS-14 (116b), as a potent pan-HDAC inhibitor and an HDAC6-insensitive inhibitor, respectively (Figure 17).(139)
Figure 17
Figure 17. Late-stage functionalization using C–H diversification reactions and cytochrome P450 enabled rapid identification of HDAC inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and phosphodiesterase 2 inhibitors.
In 2015, a stereodivergent and step-economical diversification of the privileged 2-arylcyclopropylamine motif by sequential C(sp3)-H borylation and Suzuki–Miyaura coupling was developed.(140) Then, in 2017, El Marrouni et al. described the successful application of a palladium-catalyzed C(sp2)–C(sp3) cross-coupling reaction of a fully elaborated inactivated organostannane compound 118 with a range of aryl halides to achieve rapid, parallel synthesis of HIV non-nucleoside reverse transcriptase inhibitor 119 from doravirine (117) (Figure 17).(141)
The palladium-catalyzed cross-coupling reaction between N-tosylhydrazones and heteroaryl halides constitutes a rapid and efficient approach to the preparation of 1,1-diarylethylenes as novel heterocyclic analogues of iso-Combretastatin-A4 (isoCA-4). Among them, 120 induced G2/M cell cycle arrest. It also exhibited interesting potency against CA-4-resistant colon carcinoma cells and multidrug-resistant leukemia cells, high human microsomal stability (in comparison to isoCA-4), and central nervous system (CNS) permeability.(142)
Direct functionalization of complex molecules still faces several challenges as chemical reactions with high selectivity, high yield, and mild reaction conditions are required. Somewhat unexpectedly, it was found that the number of reactions, dominating the chemical landscape of contemporary medicinal chemistry, is very limited.(143) To expand the chemical space and structure diversity of compound libraries and to facilitate the late-stage derivatization of several complex pharmaceutical compounds, there is a need to develop more LSF compatible reactions that prepare functional compounds with desirable properties.(144,145) Novel organic catalysts and synthetic methodology (including photochemistry and electrochemistry) are particularly promising for late-stage derivatization of complex molecules.(146−148) Sulfur(VI) fluoride exchange (SuFEx) reaction, which relies on readily available building blocks to afford molecules with the sulfonyl fluoride motif, has also expanded the toolbox of organic and medicinal chemists.(149−151)
Metabolomics has been applied not only in the drug discovery process and personalized medicine but also in lead diversification.(152) In 2018, Obach et al.(153) described a rapid and cost-effective late-stage lead functionalization method, whereby lead compounds can be converted into new derivatives by using liver microsomes at a submicromolar scale. Several representative human phosphodiesterase-2 inhibitors were incubated with liver microsomes from various organisms to afford multiple products, which were isolated and analyzed by quantitative cryomicroprobe NMR (qNMR) spectroscopy. The diluted solutions from qNMR analysis were subjected to biochemical assays, which yielded compounds PF-06815189 (124), 125, and 126 with improved potency inhibiting phosphodiesterase-2, physicochemical profile, and favorable metabolic properties, compared with the respective parent molecules 121–123 (Figure 17).(153) The examples highlighted herein illustrate the value of organic and biocatalytic C–H functionalization methods in drug discovery.(154)
5. Multiparameter Optimization
ARTICLE SECTIONS
A high-quality drug should exhibit a good balance of efficacy against its therapeutic targets, physicochemical properties, ADME properties (absorption, distribution, metabolism, and elimination) and safety.(155,156) In other words, drug discovery is a multiparameter optimization (MPO) process in which the aim is to find novel pharmaceutical molecules that meet the multiple drug-like criteria. Examples are “rule of 5”, “beyond rule of 5”, and “lead-like drugs”(157−160) and ligand efficiency metrics (such as lipophilic efficiency).(161) Half of all therapeutic targets cannot be modulated with small-molecules that comply with the rule of 5. Macrocycles have been found to be in “beyond rule of 5” space and were especially useful in drugging targets that have large, flat, or groove-shaped binding sites.(158)
Avoidance of toxicity and optimization of drug-like properties is a critical issue at the late stage of drug discovery.(162) Thus, in drug optimization, structure–property (or toxicity) relationship studies should be focused on a range of targets, not merely activity.(163,164)
Drug discovery for the CNS disorders still faces huge challenges, for example, the optimization of lead compounds into drug candidates is difficult due to the strict physicochemical properties required to penetrate the blood–brain barrier. In 2010, a druglikeness CNS MPO algorithm was designed by Pfizer, which has parametrized medicinal chemistry design space for CNS drug candidates.(165a) Since then, significant progress has been made in application of this simple-to-use design algorithm.(165b,c)
The significance of understanding the kinetics of the interaction between a ligand and its target has been acknowledged for a long time. Ligand–target residence time (structure–kinetic relationship, SKR) has also been valued as a key drug discovery parameter, and it is still receiving sustained attention. Numerous recent research articles from the medicinal chemistry community provide compelling arguments for more widespread assessment of binding kinetics and discussion of SKR.(166−169)
The binding of ligand with target is influenced by multiple factors, including hydrogen bonds and hydrophobic interactions, residual mobility, desolvation, dynamics, and the local water molecule.(170) Experimental tools to (un)binding kinetics are nowadays available,(171) but reliable computational methods for predicting kinetics and residence time are still lacking. Most attempts have involved molecular dynamics (MD) simulations, which are CPU-intensive and not yet particularly accurate.(172,173)
In 2016, Mollica et al. reported a new scaled-MD-based protocol, verified by directly comparing computational predictions, experimental kinetics measurements, and X-ray crystallography, which seems to have potential for predicting kinetics and drug residence times in drug discovery.(174) In considering structure–property–activity relationships, multiple aspects of ligand–protein binding need to be considered, including surface water networks coating protein-bound ligands(175) and water-mediated ligand functional group cooperativity.(176)
Off-rate screening by surface plasmon resonance (SPR) is an efficient approach to kinetically sample the hit-to-lead chemical space using unpurified reaction products.(177,178) Recent study demonstrated that the lifetime of the drug–target complex is governed by interactions in the transition state for ligand binding rather than the ground state of the enzyme–ligand complex, and the on-rates can play a key role in drug–target residence time.(179) In 2018, an efficient computational method, for the ranking of drug candidates by their residence time and giving insights into ligand–target dissociation mechanisms, was reported.(180)
Innovations in characterizing lead quality and compound prioritization have allowed more informed decision-making by medicinal chemists.(181) We anticipate that these new methodologies and technologies will dramatically improve the efficiency of early stage drug discovery.
6. Biological System-Mediated Drug Delivery
ARTICLE SECTIONS
6.1. Antibody-Recruiting Molecules
Synthetic immunology, i.e., the development of synthetic systems to modulate immunological functions, is a newly established field. One focus of research has been to find synthetic small-molecular agents, named antibody-recruiting molecules (ARMs), that can enhance antibody binding to disease-relevant viruses or cells, thus promoting their immune-mediated clearance.(182,183)
Early in 2009, Spiegel et al. reported several ARMs that target prostate cancer.(184) They designed new bifunctional ARMs to bind to HIV-1 gp120 and antidinitrophenyl (DNP) antibodies, simultaneously. Anti-DNP antibodies are abundant in the human bloodstream. By connecting these two fragments together, ARMs (exemplified by 128, derived from the existing molecule 127 (BMS-378806)) could mediate the formation of a ternary complex, leading to blocking virus entry and antibody-mediated immune clearance of gp120-bearing cells (Figure 18).(185a)
Figure 18
Figure 18. Antibody-recruiting small molecules 128 and 130 that target HIV gp120 and 131 that targets prostate-specific membrane antigen.
In 2014, computationally driven modification of ARMs targeting HIV-1 gp120 gave an optimized molecule 130 (derived from 129), which was almost 1000-fold more potent than 128 in gp120-binding and cell-based antiviral assay. It was also effective against multiple HIV pseudotypes in laboratory and clinic.(185b)
In 2016, Genady et al. reported the discovery of radiolabeled ARMs (exemplified by 131) that target prostate-specific membrane antigen and anti-DNP antibodies for combined immunotherapy and radiotherapy.(186)
6.2. Human Serum Albumin-Derived Drug Delivery
Human serum albumin (HSA) is the most abundant protein in sera (30–50 g/L human serum), where it primarily functions as a natural transporter for a myriad of molecules. Being an intrinsic protein of the human blood, it exhibits no immunogenicity. It also has a long circulatory half-life (about 19 days) due to its binding affinity for the recycling neonatal Fc receptor. Thus, HSA is an ideal drug carrier for targeted delivery and for improving the pharmacokinetic profile (half-life extension) of drugs.(187−190) Several albumin-related small-molecular drug delivery technologies have been developed, including in vivo noncovalent or covalent endogenous HSA targeting, coupling of small molecule drugs to exogenous albumin, and encapsulation of drugs into albumin coated nanoparticles.(187)
Most small-molecular drugs are short-lived species in the circulatory system and can be rapidly eliminated via glomerular filtration. Noncovalent binding of small-molecular drugs to HSA could protect them against enzymatic degradation and renal clearance, affording slower clearance and a prolonged half-life in vivo.
For example, FMS(3)-gentamicin (133) was developed as a long-acting prodrug derivative by linking three (2-sulfo)-9-fluorenylmethoxycarbonyl (FMS) moieties to three amino moieties of gentamicin (132) to provide increased affinity for albumin.(191) Compound 134 is a fatty acid-like platinum(IV) prodrug designed to improve drug delivery via enhanced interaction with HSA.(192) The clinically relevant glucagon-like peptide 1 (GLP-1) was functionalized with diflunisal (135, albumin binder) and indomethacin (136, albumin binder) to afford a divalent GLP-1 analogue 137 with a longer circulatory half-life and absorption time compared to its monovalent equivalent (Figure 19).(193)
Figure 19
Figure 19. Examples of the in vivo noncovalent endogenous HSA targeting approach.
Kratz et al. established an in vivo covalent conjugation strategy that exploits endogenous HSA as a drug carrier. In this approach, the prodrug binds selectively and rapidly to the cysteine-34 residue on the surface of HSA after intravenous administration, thereby generating an in situ transport form of the drug in the blood (Figure 20A,B).
Figure 20
Figure 20. (A) X-ray structure of human serum albumin (bound with diflunisal, PDB ID 2BXE): the position of cysteine-34 is highlighted. (B) Schematic illustration of in vivo thiol–maleimide conjugation. (C) Chemical structure of doxorubicin-maleimide derivative 138, gemcitabine-maleimide derivatives 139 and 140, and albuvirtide.
A proof-of-concept was obtained with the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (138, DOXO-EMCH, INNO-206), which is the first albumin-binding prodrug of doxorubicin to enter clinical trials. Compound 139 selectively binds to circulating albumin within just a few minutes (Figure 20C).(194) Inspired by translational research with 138, many albumin-binding prodrugs have been developed, as exemplified by recently reported in situ covalent-albumin-binding gemcitabine prodrugs 139 and 140, which offer improved bioavailability and tumor accumulation (Figure 20C).(195) Notably, compound 139 demonstrated remarkably increased bioavailability (21-fold higher than gemcitabine) and efficient tumor accumulation of free-gemcitabine (8-fold greater than gemcitabine).
On 6 June 2018, Albuvirtide (141, ABT), a HIV fusion inhibitor developed by Frontier Biotech, was approved as a new anti-HIV drug in China, with long half-life in vivo (suitable for injection once a week) and potent and broad-spectrum potency against HIV-1 variants resistant to T20.(196) ABT is a 3-maleimimidopropionic acid-modified peptide that can irreversibly conjugate to HSA.(197)
The macromolecular prodrug strategy of in vivo HSA conjugation is effective to overcome rapid enzyme inactivation, extended half-life (exemplified by ABT), and poor tumor targeting of cytotoxic anticancer agents. It also offers several advantages over in vitro-synthesized drug albumin conjugates: (a) it avoids the need for carefully controlled purification of commercial albumin; (b) the prodrug is relatively inexpensive to manufacture and convenient to store and use; and (c) quality control is simple, being comparable to that needed for any other small-molecular drug candidate.
6.3. “Bio-oxidizable” Prodrug Strategy
To improve the efficiency and reduce side effects (arising from peripheral cholinergic activation) of approved acetylcholinesterase (AChE) inhibitors during symptomatic treatment of Alzheimer’s disease (AD), Levacher et al. reported a biological investigation of new AChE inhibitors based on a novel “bio-oxidizable” prodrug approach.(198) The design of this “bio-oxidizable” prodrug originates from an insight into the action mechanism of AChE inhibitors. Whereas donepezil (142) and galanthamine (143) are competitive inhibitors, rivastigmine (144) is a pseudoirreversible inhibitor via the carbamylation of the serine-OH located at the “esterasic site” of AChE. All these drugs share in common a tertiary amine moiety that plays an important role in the inhibition of AChE. At physiological pH, this amine was protonated as a positive charge bioactive form, which binds to the “catalytic anionic site” of AChE (Figure 21). Generally, the charged form cannot cross the blood–brain barrier through passive diffusion; the acid–base equilibrium permitted the neutral inactive form to penetrate this physiological barrier, which resulted in both central and peripheral cholinergic effects often observed with these drugs. Based on these mechanistic insights, by temporarily masking the positive charge at the periphery, a “bio-oxidizable prodrug” strategy was envisaged to design central specific AChE inhibitors, which afforded dihydroquinoline carbamate 1a and donepezil-based “bio-oxidizable” prodrugs 1r.
Figure 21
Figure 21. (A) Approved AChE inhibitors for the symptomatic treatment of AD and schematic representation of the ligand binding site of AChE; the “anionic” and “esterase” sites are highlighted. (B) Rational design of central selective AChE inhibitors via a “bio-oxidizable” prodrug approach.
Putatively, once in the CNS, the prodrugs 145a and 146a should be converted into the parent compounds 145b and 146b through a redox-activation process mediated by the NAD(P)H/NAD(P)+ coenzyme system. It is expected that the presence of a permanent positive charge in 145b and 146b could not only act as AChE inhibitors in the CNS through “locked-in” effect but also facilitate rapid elimination of the quinolinium salt form in the peripheral system. These studies strongly prove that this attractive “bio-oxidizable” prodrug strategy is ingenious and practical.
6.4. Mitochondrial-Targeted Agents
Cancer cells principally show higher mitochondrial transmembrane potential and abnormal metabolic pathways. Thus, the targeting and delivery of anticancer agents to the mitochondria could improve therapeutic efficacy.(199) This mitochondrial-targeted strategy was exemplified by introduction of delocalized lipophilic cations to the parent compounds. The most investigation-delocalized lipophilic cation is the triphenylphosphonium cation, and several successful examples have been reported with remarkable cytotoxicity and selectivity, including chlorambucil derivative 148 (Mito-Chlor)(200) and lupane triterpenoid derivative 150 (Figure 22).(201a) Additionally, a recent study demonstrated that conjugation with triphenylphosphonium cation can restore the antifungal activity of some natural terpenes.(201b)
Figure 22
Figure 22. Mitochondria-targeted anticancer agents.
7. Structure-based Drug Discovery
ARTICLE SECTIONS
Structure-based drug discovery is a fundamental strategy for finding and optimizing lead compounds of therapeutic importance. This section will discuss the following topics: covalent inhibitors or probes, bisubstrate inhibitors, exploration of water-binding pockets, and drug design to stabilize inactive protein conformations, as these have been highlighted in very recent literature.
7.1. Covalent Inhibitors or Probes
An attractive increase in the potency and pharmacokinetics of a drug-like compound is to evoke the formation of a covalent bond. Compared with noncovalent inhibitors, the advantages of covalent compounds lie in the following aspects: higher potency, long residence time, and decreased drug resistance. In the past several years, many covalent drugs such as telaprevir, abiraterone, carfilzomib, and afatinib have been used in clinical, ushering in a new era for covalent modifiers.(202,203)
Covalent inhibitors should remain a key focus of contemporary drug discovery, especially in the initial structure-based design optimization, as exemplified by human tissue transglutaminase inhibitor 151,(204) c-Jun N-terminal kinase 3 inhibitor 152,(205) janus kinase 3 selective inhibitor 153,(206) KRAS inhibitor ARS-853 (154),(207) FGFR inhibitor 155 (PRN1371),(208) mitogen-activated protein kinase kinase 7 (MKK7) inhibitor 156,(209) EGFR inhibitor 147,(210) histone lysine demethylase KDM5A inhibitor 158,(211) pyruvate dehydrogenase kinase 1 (PDK1) inhibitor 159,(212) and monoacylglycerol lipase (MAGL) inhibitors 160 and 161(213) (Figure 23).
Figure 23
Figure 23. Covalent inhibitors in drug discovery: typical examples. The warheads for covalent binding are highlighted in red.
Complementarily, allosteric modulators are sought after as a means to avoid undesirable side effects of covalent or active site inhibitors. In 2016, the first covalent and potent cannabinoid 1 receptor (CB1R) allosteric modulator 162 was reported, which can be used as an effective chemical probe for characterizing CB1R allosteric ligand-binding motifs.(214) In 2018, the first covalent positive allosteric modulator 163 for the metabotropic glutamate receptor 2 (mGlu2, a class C GPCR) was reported, which advanced the understanding of the mGlu2 PAM interaction.(215)
The main hurdle for covalent inhibitors is the lack of selectivity. Apart from selecting a warhead or modulating of electrophilic warhead reactivity, substantial efforts are required to optimize noncovalent reversible interactions to facilitate target-selective recognition and the overall potency. For example, through crystallography, kinetic, and molecular simulation studies, interaction of cyanamide-based covalent JAK3 inhibitor 164 with residue Cys909 was optimized affording potent and selective JAK3 inhibitors as exemplified by 165, with substantially enhanced activity and selectivity (Figure 24A).(216)
Figure 24
Figure 24. Discovery of covalent inhibitors via (A) optimization of noncovalent reversible interactions and (B) diversity-oriented modification of warheads.
Y181C-mutated HIV-1 strain is one of the key clinically observed mutants. In 2017, Jorgensen’s group took Y181C-mutated HIV-1 reverse transcriptase as the target for drug design.(217) Based on the protein crystallography, it was found that the carbon–chlorine bond catechol in diethers compound 166 is oriented toward Tyr181, and its replacement with an electrophilic warhead could make covalent binding of Cys181 variants. Consequently, electrophilic group-bearing compounds 167–170 were designed and synthesized. Especially, compounds 168 and 170 are covalent inhibitors of HIV-1 RT mutants (Y181C and K103N/Y181C) through in vitro assays (MT-2 cells), mass spectrometry, and protein crystallography. This is the first successful application of the irreversible covalent inhibition strategy to HIV-1 reverse transcriptase (Figure 24B).(217) Based on activity results, it is found that small chemical alterations of warheads often cause significant differences in activity. Therefore, diversity-oriented selection of warheads make possible the systematic exploration of the chemical space.(218)
Besides the most popular acrylamide, additional electrophilic traps have undergone considerable development as “privileged warheads” in chemical biology (exemplified by sulfonyl fluoride and isothiocyanate).(215,219) The exploration of warheads with chemical reactivity toward target enzymes for incorporation into parent compounds is expected to afford novel covalent drugs.
Design of boron-containing molecules has recently attracted much attention. Boron differs from carbon in that it has a vacant p-orbital that is receptive to a reversible covalent bond formation with a Lewis base under physiological conditions. Recently, boronic acid was proven a structurally and mechanistically differentiated electrophile from other cysteine reacting moieties, arising from the ability of boronic acids to generate a reversible covalent bond with oxygen nucleophiles (Lewis base) of the target protein. Boronic acid-based covalent agents have received widespread attention in the drug design community, with several boron-containing drugs (including bortezomib and ixazomib, tavaborole, and crisaborole) and other recent successful examples that have demonstrated their therapeutic effects (Figure 25).(220)
Figure 25
Figure 25. Structures of boron-containing drugs.
For many years, Raines and his team has been engaged in the research of boric acid based drug discovery and chemical biology.(221) In 2017, Raines et al. reported on boronic acid-substituted stilbenes that limit transthyretin (TTR) amyloidosis in vitro. X-ray crystallographic analysis of TTR/175 complexes (PDB code 5U4F) demonstrated that a boronic ester was reversibly formed with Ser117, which has a great contribution to the thermodynamics and kinetics of binding (Figure 26).(221a)
Figure 26
Figure 26. Structure of stilbene boronic acid 175 and its binding mode with TTR (PDB code 5u4f).
In 2018, based on the three-dimensional structure and mechanism of HIV-1 protease, this group replaced the aniline group of darunavir (176) with phenylboronic acid moiety, which led to the identification of 177 with increased affinity with the protease by 20 times and a high affinity for HIV-1 protease-resistant strain D30N (Figure 27). X-ray cocrystallization structure demonstrated that the boric acid group participated in triple hydrogen bonding, which was superior to the amino group in darunavir and other derivatives. The hydrogen bond distance between Asp30 (or Asn30) of protease and hydroxyl group of boric acid was shorter than orthodox hydrogen bonding, which had a certain degree of covalence. This is a reasonable explanation for high potency and remarkable antiresistance profiles of boric acid derivatives.(221b)
Figure 27
Figure 27. Discovery of boronic acid-bearing subpicomolar inhibitors of HIV-1 protease.
In 2007, a 100-fold affinity gain was achieved by introduction of a C-terminal boronic acid group into dipeptidic inhibitors (178a,b) of the West Nile, Zika, and dengue virus proteases. The resulting molecules (as exemplified by 179) have high binding affinity with Ki values in the two-digit nanomolar level, low cytotoxicity, and virus-inhibitory potency (Figure 28). SARs and a X-ray cocrystal structure of 179 with West Nile virus NS2B-NS3 protease pave the way for the design of advanced covalent-reversible inhibitors targeting emerging flaviviral pathogens.(222)
Figure 28
Figure 28. Discovery of 179 as a capped peptide–boronic acid inhibitor of flaviviral proteases and its binding mode with West Nile virus NS2B-NS3 protease (PDB code 5IDK).
Boronic acid transition-state inhibitors proved to be one of the most promising classes of serine amidohydrolase inhibitors, including β-lactamase inhibitors. In 2001, an unexpected tricovalent binding mode of boronic acids within the catalytic site of a penicillin-binding protein was reported.(223) The boron usually adopts a tetrahedral conformation, binds to the nucleophilic serine of the active site, and mimics the transition state of the catalytic reaction. Compound 180 (Ki = 44 nM) represented a promising lead compound against ADC-7 (Acinetobacter-derived cephalosporinase), one of the most critical resistance determinants in A. baumannii. The cocrystal structure of the ADC-7/180 complex suggested that the inhibitor was covalently linked to the catalytic residue Ser64 (Figure 29), highlighting the significance of key structural factors for recognition of the boronic acid moiety.(224)
Figure 29
Figure 29. Cocrystal structure of 180 in complex with ADC-7 β-Lactamase (PDB code 4U0X).
The risk of indiscriminate reactivity of active warheads and the resulting adverse effects can be reduced by incorporating latent electrophiles into irreversible covalent inhibitors. In general, a terminal alkyne is considered “inert” toward cellular components and is therefore often applied in bioorthogonal reactions. Recently, an alkyne moiety was introduced as a less reactive electrophilic moiety into cathepsin K inhibitors. Notably, based on crystal structure analysis, alkyne-based compounds 181 and 182 (Figure 30) effectively inhibit the activity of cathepsin K protease by formation of an irreversible covalent bond with the cysteine residue in the catalytic site in a proximity-driven manner. Just because of this, they did not show indiscriminate thiol reactivity. More importantly, based on these proof-of-concept studies, it is foreseeable that latent electrophiles such as the alkyne may be of important prospects in further design of cysteine-targeting irreversible covalent drugs with an improved safety profile.(225) Interestingly, a warhead moiety is not necessary for covalent inhibitors. For example, the cyclic piperidine and piperazine aryl ureas (piperidine-bearing PF750 (183) and piperazine-bearing JNJ1661010 (184)), without any warhead moiety, were reported as potent fatty acid amide hydrolase (FAAH) inhibitors (Figure 30) because FAAH could efficiently hydrolyze the amide bond of these molecules, forming a covalent enzyme-binder adduct.(226)
Figure 30
Figure 30. Covalent small molecule inhibitors with a latent electrophile or via a proximity-driven mode.
The binding process of covalent inhibitors with related targets consists of multiple processes, which are not necessarily independent of each other. Thus, computer-aided prediction of binding affinity for covalent inhibitors presents a great challenge. The free energy perturbation combined with λ-exchange molecular dynamics technique provided particular advantages in predicting binding selectivity among protein isoforms, which is a major challenge in covalent inhibitor design.(227) We envision that the continued interest in covalent drug discovery will propel further development of new computer programs to predict the binding energetics and binding mode of covalent drugs.(228)
Generally speaking, diversity-oriented structural modification can compensate for the shortcomings of target-based drug design and computational prediction. Under this situation, a fragment-based method combined with a MS covalent ligand screening was developed to discover irreversible covalent inhibitors of cysteine proteases, such as ubiquitin ligase.(229,230)
7.2. Bisubstrate Inhibitors
A bisubstrate inhibitor consists of two covalently connected fragments, each targeting either the substrate or the cofactor binding pocket, thus potentially mimicking the ternary transition state of a bireactant catalytic reaction. This drug design approach has the potential to obtain high potency and selectivity. More than a decade ago, several bisubstrate inhibitors were successfully developed for several proteins, including kinases and acetyltransferases.(231,232)
There have been some new developments in recent years. Mycobacterial biotin protein ligase (MtBPL) is an indispensable enzyme in Mycobacterium tuberculosis (Mtb) and regulates lipid metabolism via the post-translational biotinylation of acyl coenzyme A carboxylases (ACCs). The enzymatic reaction proceeds in two steps by sequential adenylation of biotin (185) to generate Bio-AMP (186), followed by acylation of the biotin carboxylase carrier protein domain of ACCs to afford holo-ACC (187). In 2015, nucleoside-based bisubstrate adenylation MtBPL inhibitors 188 and 189 were discovered, through modifications on the ribofuranosyl ring of the nucleoside (Figure 31A).(233)
Figure 31
Figure 31. (A) Targeting MtBPL with nucleoside-based bisubstrate adenylation inhibitors. (B) Schematic representation of the transition state of DNMT (DNMT1 and DNMT3A) catalytic site and the chemical modulation strategy. In red is depicted the methyl-donor AdoMet and its mimic 4-aminoquinazoline, in blue the deoxycytidine in the DNA and its analogues, and in pink the linker between the two moieties. Besides, the amino moiety in C4 position of the quinazoline was substituted by phenylpropylamine as a hydrophobic group on the amine at C4 position of the adenosine in AdoMet analogues, which was probably favorable for DNMT inhibition potency. (C) Discovery of a bisubstrate inhibitor of NNMT.
In 2017, on the basis of the structure of the catalytic pocket of DNMT (Figure 31B), the bisubstrate analogues-based inhibitors were designed, by mimicking each substrate of DNA methyltransferases (DNMT3A and DNMT1), the S-adenosyl-l-methionine (190, SAM), and the deoxycytidine, and linking them together, which resulted in quinazoline-quinoline-derived DNMT3A and DNMT1 inhibitors 191 and 192, some showing certain isoform selectivity.(234)
Inspired by the recently published ternary crystal structure of human nicotinamide N-methyltransferase (NNMT) in complex with the substrate nicotinamide (193) and the cofactor SAM as the methyl group donor, a bisubstrate NNMT inhibitor MS2734 (194) was discovered and characterized (Figure 31C). Furthermore, a cocrystal structure of 194 in complex with hNNMT was obtained, which paved the way for further developing more potent and selective NNMT inhibitors.(235)
7.3. Exploring Water-Binding Pockets (Structural Water Molecules) in Structure-based Design
Water molecules are important components in protein channels and are often found around ligands in protein crystal structures. Water-mediated interactions, especially hydrogen bonds, play key roles in drug binding.(236,237) Careful examination of these water molecules and their energetics can contribute to successful drug design, as exemplified by neuronal nitric oxide synthase inhibitors, nonpeptidic urea HIV protease inhibitors, and benzoxaborole non-nucleoside polymerase inhibitors of HCV.(238−240)
Recently, several structural and computational studies to explore water-binding pockets have been reported.(241−244) One way to systematically improve existing weak binders could focus on identifying and later chemically optimizing those moieties with a particular proximity or orientation to water molecules in the protein–binder complex. For example, the X-ray structure of the antiviral drug Arbidol (195) with influenza hemagglutinin revealed a highly ordered water molecule adjacent to Arbidol, and this was exploited in the structure-based design of Arbidol analogues (Figure 32). Addition of a meta-hydroxyl group to the thiophenol group of Arbidol to replace the water molecule in the binding pocket afforded 196, which showed significantly increased affinity for both H1 (98-fold) and H3 (1150-fold) hemagglutinin subtypes.(245)
Figure 32
Figure 32. Structure-based optimization based on the X-ray structure of Arbidol bound to influenza virus hemagglutinin (H3-HK68: A/Hong Kong/1/1968; PDB code 5T6N).
A recent study indicated that the introduction of a hydroxyl group to form a water-mediated hydrogen bond may not necessarily improve the binding affinity between ligand and target because hydrophobic effects also play an important role in ligand binding affinity in some cases.(246)
The M2 proton channel of influenza A is a well-validated target for the antiviral drugs, such as amantadine and rimantadine. Recent disclosed X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that the inhibitors engage in and disrupt transmembrane networks of hydrogen-bonded water and that small molecules can enable potent inhibition by targeting key water molecules.(247)
Generally, it is thought that a protein binder can achieve affinity by extending into a region occupied by unfavorable water molecules or lose affinity by displacing water molecules from a region where it was relatively stable. However, the real situation is much more complicated. The prevailing thermodynamic theories of the past few years claim that water was observed largely in terms of an entropic gain after it was displaced by a ligand, which are now known to be too idealistic. In most cases, as water molecules can be difficult to locate by X-ray diffraction methods, especially when they are not tightly bound to biomacromolecules, NMR spectroscopy can be used as a valuable technique to assess those water molecules. By increasing the (perdeuterated) protein concentration, WaterLOGSY titration experiments help to get useful information about the location of protein-bound water in the surroundings of the ligand and ligand binding modes even in the case of weak binders, which are extremely beneficial to specific optimization of the ligand to enhance binding affinities.(248)
In view of the complexity and uncertainty of water-mediated interaction, the understanding of water’s roles in the underlying structural protein–ligand complexes came at the expense of very careful and detailed dissections of the relevant scenarios with new computational methodologies and isothermal calorimetric, spectroscopic, and crystallographic experiments.(249)
7.4. Stabilization of Protein Inactive Conformations or Protein–Protein Interactions
A large number of medicinal chemists have engaged in the design and development of protein kinases inhibitors. However, in comparison, targeting protein kinases with small compounds that bind outside the highly conserved ATP pocket to stabilize inactive protein conformations has been regarded as a fresh approach in kinase-targeted drug design that is worthy to be promoted because these compounds often have improved pharmacological profiles compared to inhibitors exclusively targeting the ATP pocket. However, traditional screening approaches for kinase inhibitors are often based on enzyme activity, and it has been recognized that they may miss ligands that stabilize inactive protein conformations. An example of a way to overcome this issue is provided by a study to find selective Met tyrosine kinase inhibitors in which a high-throughput virtual screening of a ChemNavigator compound database was employed for directed discovery of inhibitors targeting the Met tyrosine kinase domain (i.e., compounds that stabilize the kinase domain in its inactive conformation).(250)
In 2010, Klüter et al. reported a kinase binding assay using a pyrazolourea type III inhibitor and enzyme fragment complementation technique that is suitable to screen stabilizers of enzymatically inactive kinases.(251) In the same year, Whelligan et al. reported the first systematic exploration of compounds binding to an unusual, inactive conformation of the mitotic kinase Nek2.(252)
Recently, a novel series of competitive shikimate kinase inhibitors that stabilize an inactive open conformation of the enzyme by targeting the dynamic apolar pocket surrounding the natural substrate was disclosed.(253)
Novel pleckstrin homology domain-dependent covalent-allosteric inhibitors of the kinase Akt were identified via structure-based design, which bind covalently to a distinct cysteine residue of the kinase and stabilize the inactive protein conformation.(254) To sum up, stabilization of an inappropriate and inactive conformation for enzymatic catalysis seems an innovative and promising approach for dissecting conformation-dependent signaling of protein kinases and finding drug candidates.(252) Certainly, there is a significant challenge to adapt screening methodologies and downstream techniques to identify and optimize stabilizers of inactive conformations.
Similarly, stabilization of protein–protein interactions is also a viable strategy for drug discovery but has not been exploited in a systematic manner. Ottmann’s lab has pioneered this field.(255) The potential for high selectivity, the ability to gain access to previously undruggable targets, and the list of impressive compounds were reviewed recently.(256)
8. Conclusions and Prospects
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Contemporary drug discovery still faces major scientific and economic challenges to identify and provide lead compounds in an efficient manner. The classical methods of drug design, preparation, and evaluation lead to substantial time delays, resulting in inefficient usage of data in the complex drug design process. This Perspective has focused on exploring strategic approaches to solving issues in lead identification and optimization projects that affect candidate development and quality and that are frequently encountered in drug development campaigns (Figure 33).
Figure 33
Figure 33. Schematic diagram of interdisciplinary teamwork at the interface between the field of chemistry and biology with the aid of informatics.
Structure-based drug design intends to generate the protein and ligand molecules that have high affinity and specificity. Since the binding cavity of an identified drug is usually large and their possible protein interactions are still required to be explored, detailed understandingd of drug–protein interactions or selectivity-determining features are needed to increase the effectiveness of structure-based drug design. Precise knowledge of (non)covalent interactions between proteins and binders provides good foundations for rational design of covalent inhibitors, bisubstrate inhibitors, stabilizers of protein inactive conformations, and exploitation of the water-binding pocket (structural water molecules) for structural modification. Notably, covalent inhibitors attract tremendous attention. One advantage of covalent drugs is a reduced risk for the development of resistance, which is a major challenge in the treatment of cancer and infectious diseases. The key factor affecting the target specificity of covalent inhibitor is the warhead moieties’ reactivity. The ideal warhead moieties should be stable under physiological conditions and eliminate the off-target reaction with undesired biological targets as far as possible. Undoubtedly, target-induced covalent inhibitors (a proximity-driven reactivity) are an ideal type.
Despite the huge information contributed by academia and industry in the past decades, a rational approach using the structure-based drug design with the aid of computational methods remains challenging. There are large flexible variations in the process of protein–ligand binding: there can be, beyond the protein and ligand, cofactors and solvent molecules that should be observed. Additionally, entropic contributions can be important because the protein and ligand often possess significant flexibility.(223) In an recent study, the role of protein conformational entropy and the response of water molecules located around the binding sites and ligand are highlighted in detail.(257)
In most cases, drugs are identified from the biological screening of compound collection, followed by hit to lead optimization toward functional end points. A large number of failures in the late stages of drug development underlines the point that drug discovery is a multiparameter optimization process, and multiple properties should be enhanced to reach the stage where a molecule could be considered for in vivo studies. However, if a lead compound is not considered to be efficient, it will never transform to a drug candidate, irrespective of other properties, which makes the structure–activity and structure–property relationships as a central task during early to midstages of lead optimization. Structural diversity within chemical libraries increases the probability of identifying a lead molecule. In phenotype-based drug discovery, molecular diversity is even more significant due to absence of target information. Consequently, the features of screening collections are often balanced between diversity, physicochemical desirability, intrinsic complexity, and synthetic feasibility. Even then, multiparameter optimization of the lead compound for efficacy and drug-like properties is challenging not only because of synthetic considerations but also because of the limited ability to predict how compounds will interact with complex biological systems. Given the complexity of lead optimization, this process is mainly driven by knowledge, intuition, and experience. In this stage, diversity-oriented synthesis-facilitated medicinal chemistry with combinations of many cheminformatics tools, as exemplified by hierarchical multiple-filter database screening (in silico ADMET prediction), is an attractive strategy.
Innovations in synthetic methodologies (exemplified by LSF), synthetic chemistry techniques (microwave chemistry, continuous flow synthesis, automated synthesis, and purification methods), and development of modular, convergent synthetic reactions (“build-couple-pair” approach, bioorthogonal reactions, cascade reactions, multicomponent reactions, and late-stage microsomal oxidation) have enabled the diversity-oriented, synthesis-facilitated medicinal chemistry, which can greatly facilitate the construction of diverse and drug-like compound libraries.(258−260) As exemplified by bioorthogonal chemistry and photoactivatable-inspired drug discovery, a strong communication between synthetic and medicinal chemists could allow greater impact of novel methodologies and expand the synthetic toolbox of medicinal chemistry in future drug discovery.
Drug repositioning has emerged as an alternative approach to the traditional drug discovery and development due to its efficiency in cost and time. Historically, this approach was accomplished by serendipitous discoveries and the exploitation of unintended side effects. Core concepts that support drug repurposing using network strategies include drug–target interactions, target–disease associations, and drug–indication associations. On the basis of medically inspired phenotypic screening and the modern mechanism-of-action methods, drug repositioning will continue to promote drug discovery.(261) Meanwhile, computational (network-based) repositioning strategies are becoming increasingly popular. However, it should also be noted that the potential of the drug repurposing strategy has not been as widely realized as had been hoped, in part owing to legal and regulatory barriers.
Similarly, “over-represented” features of “privileged structures” in drug-like molecules enable us to design isosteres with structural diversity by maintaining the core physicochemical properties. Focused libraries of privileged scaffolds can expand the molecular diversity of synthetic collections. The strategy of “privileged structure” repositioning has been extensively employed to exploit additional bioactivities by rapid derivatization of key intermediates with well-established synthetic protocols. We envision that fragment-based lead discovery methodology and computational chemistry will significantly facilitate the exploitation of privileged motifs.
The “precise” drug delivery is one of the pivotal aspects of contemporary drug development. Notably, drug delivery systems with high temporal and spatial precision using bioorthogonal uncaging strategies, photoactivatable chemistry, antibody-recruiting molecules, and human serum albumin-derived drug delivery have received significant attention during the past few years, which reflects the deep integration of medicinal chemistry and biology. Challenges such as nonspecific binding, accumulation, degradation, or renal clearance require the development of innovative drug delivery systems that are capable of selective targeting and real-time monitoring of drug release. Bringing the two disciplines chemistry and biology closer and diminishing the boundaries creates new opportunities to identify new drug delivery systems. What can not be ignored is the use of proteolysis-targeting chimeras (PROTACs), which induce selective degradation of specific target proteins through the ubiquitin–proteasome system, found as a novel, though well-known, drug discovery strategy with the capability to offer unique therapeutic advantages, compared with the present approaches.(262) Relevant research papers and reviews are abundant, so this is not covered in this Perspective.
All in all, the main goal of medicinal chemists is to change the drug discovery process to become more efficient by reducing the number and duration of design cycles required to optimize lead compounds into safe and efficacious drug candidates. No single strategy is likely to be a universal panacea.(263,264) The successful development of innovative drugs requires interdisciplinary teamwork at the interface between chemistry, biology, and informatics and multiple techniques working in concert (Figure 18).(265) For example, medicinal chemists are deploying artificial intelligence (machine learning) to discover drugs, which will accelerate the productivity of the drug discovery process via automated compound optimization.(266,267) We hope this Perspective will contribute to overcoming the problems associated with drug discovery campaigns by summarizing the many ideas and strategies that are available to researchers in the field.
Author Information
ARTICLE SECTIONS
- Vasanthanathan Poongavanam - Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, DK-5230 Odense M, Denmark; Present Address: Biomedicinskt Centrum (BMC), Department of Chemistry, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden;
http://orcid.org/0000-0002-8880-9247;
- Peng Zhan - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. China;http://orcid.org/0000-0002-9675-6026;
- Dongwei Kang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. China;http://orcid.org/0000-0001-9232-953X
- Jian Zhang - Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Ji’nan, Shandong, P. R. China;http://orcid.org/0000-0002-5668-2974
- Vigneshwaran Namasivayam - Pharmaceutical Institute, Pharmaceutical Chemistry II, University of Bonn, 53121 Bonn, Germany;http://orcid.org/0000-0003-3031-3377
- Jacob Kongsted - Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, DK-5230 Odense M, Denmark;http://orcid.org/0000-0002-7725-2164
- Erik De Clercq - Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium;http://orcid.org/0000-0002-2985-8890
These authors contributed equally. All authors contributed to writing the manuscript. All authors have given approval to the final version of the manuscript.
Biographies
ARTICLE SECTIONS
Gaochan Wu
Gaochan Wu received his bachelor’s degree in pharmacy from Hebei University, China, in 2016. Currently, he is a master graduate student in medicinal chemistry at the School of Pharmaceutical Sciences, Shandong University, working under the supervision of Professor Xinyong Liu and Associate Professor Peng Zhan. His work focuses on the discovery of novel anti-AIDS agents based on rational drug design and combinatorial chemistry approaches.
Tong Zhao
Tong Zhao graduated from Shandong University with his B.S. degree in 2015. Since September 2016, he has been working in the School of Pharmaceutical Sciences of Shandong University as a Ph.D. candidate, supervised by Professor Xinyong Liu. His research interests focus on rational design, synthesis, and biological evaluation of novel potent inhibitors of URAT1.
Dongwei Kang
Dongwei Kang graduated from the School of Hebei University of Technology with his BS degree in 2012. He earned his M.S. degree and Ph.D. in medicinal chemistry from Shandong University in 2015 and 2018, respectively. He is currently working as a postdoctoral researcher in the Department of Medicinal Chemistry of the School of Pharmaceutical Sciences at Shandong University.
Jian Zhang
Jian Zhang received his Master’s degree from Shandong Normal University in 2010 and then worked in a pharmaceutical company from 2010 to 2014. Since September 2014, he has been working in the School of Pharmaceutical Sciences of Shandong University as a Ph.D. candidate, supervised by Professor Xinyong Liu. His research interests focus on rational design, synthesis, and biological evaluation of novel potent inhibitors of influenza virus neuraminidase.
Yuning Song
Yu’ning Song graduated from China Pharmaceutical University in 2007. Then she earned her M.S. and Ph.D. in pharmacology from Shandong University in 2008 and 2010, respectively. She is currently working as a licensed pharmacist in the Department of Clinical Pharmacy, Qilu Hospital of Shandong University.
Vigneshwaran Namasivayam
Vigneshwaran Namasivayam is a senior research scientist at Pharmaceutical Institute, University of Bonn, Germany (since 2010) and involved in the field of cheminformatics, computational chemistry, data analysis, and molecular modeling. He gained his doctoral degree under the supervision of Prof. Dr. Hans-Jörg Hofmann from Leipzig University, Germany (2009). He carried out his postdoctoral research at the Technical University of Munich, Germany (2010). Prior to his doctoral studies in Germany, he worked as a Research Executive (2004–2006) at Orchid Chemical and Pharmaceutical Limited, Chennai, India.
Jacob Kongsted
Jacob Kongsted completed his Ph.D. in theoretical and computational chemistry at the University of Copenhagen in 2005, followed by postdoctoral training at Lund University (Sweden) and University of Aarhus (Denmark). In 2009, he moved to University of Southern Denmark as an Assistant Professor, and from 2015, he has been Full Professor of computational quantum chemistry at the University of Southern Denmark. Kongsted has a broad research interest in theoretical and computational chemistry and has especially contributed to this field by development of novel quantum chemistry embedding methods as well as the application of these computational models to systems of biophysical and biochemical interest. In recent research, he is using quantum chemistry methods for rational design of light-induced biological functional materials and advanced drug design.
Christophe Pannecouque
Christophe Pannecouque graduated in pharmaceutical sciences at the Rega Institute for Medical Research of the Katholieke Universiteit Leuven in 1990. He obtained his Ph.D. in medicinal chemistry at the same university in 1995 and joined the group of Professor Erik De Clercq as a postdoctoral fellow. In 2003, he became an associate professor. In the field of virological research, he has unravelled the modes of action of several classes of new products with anti-HIV activity. Recently, his research has been focused on cellular targets interfering with HIV replication and on regulation of the (cyto)pathogenicity of the virus.
Erik De Clercq
Erik De Clercq has MD and Ph.D. degrees and has taught at the Katholieke Universiteit Leuven (and Kortrijk) Medical School, Belgium, where he was Chairman of the Department of Microbiology and Immunology until September 2006. He is currently Emeritus Professor of K.U. Leuven University, Member of the Belgian (Flemish) Royal Academy of Medicine and the Academia Europaea, and Fellow of the American Association for the Advancement of Science. In 2008, he was elected European Inventor of the Year (Lifetime Achievement Award), and in 2010, he, together with Dr. A. S. Fauci, was Laureate of the Dr. Paul Janssen Award for Biomedical Research. He is the (co)inventor of a number of antiviral drugs (valaciclovir, brivudin, cidofovir, adefovir, and tenofovir).
Vasanthanathan Poongavanam
Vasanthanathan Poongavanam obtained his Ph.D. in Medicinal Chemistry at the Faculty of Pharmaceutical Sciences, University of Copenhagen on computational modeling of Cytochrome P450–ligand interactions (2007–2010), followed by postdoctoral training at University of Vienna, Austria (2011–2012) and Southern Denmark University, Denmark (2013–2015). Currently, he is working as a researcher at Uppsala University, Sweden. His research activities involve prediction of ADMET properties and drug design using the cheminformatics, biomolecular simulation, and computational chemistry approaches.
Xinyong Liu
Xinyong Liu received his B.S. and M.S. degrees from the School of Pharmaceutical Sciences, Shandong University, in 1984 and in 1991, respectively. From 1997 to 1999, he worked at the Instituto de Quimica Medica (CSIC) in Spain as a senior visiting scholar. He obtained his Ph.D. from Shandong University in 2004. He is currently a full Professor of the Institute of Medicinal Chemistry, Shandong University. His research interests include rational drug design, synthesis, and antiviral evaluation of a variety of molecules that interact with specific enzymes and receptors in the viral life cycle. Other ongoing programs include studies of the molecular modification and structure–activity relationships of some natural products used to treat cardiovascular diseases, and drug delivery research using PEGylated small-molecular agents.
Peng Zhan
Peng Zhan obtained his B.S. degree from Shandong University, China, in 2005. Then he earned his M.S. degree and Ph.D. in medicinal chemistry from Shandong University in 2008 and 2010, respectively. He subsequently joined the research group of Professor Xinyong Liu as a Lecturer (2010–2012). From 2012 to 2014, he worked as a Postdoctoral Fellow funded by JSPS (Japan Society for the Promotion of Science) in the Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan. He is currently an associate professor in the Institute of Medicinal Chemistry, Shandong University. His research interests involve the discovery of novel antiviral, anticancer, and neurodegenerative diseases-related agents based on rational drug design and combinatorial chemistry approaches.
Acknowledgments
ARTICLE SECTIONS
We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC Nos. 81573347, 81603028), Young Scholars Program of Shandong University (YSPSDU No. 2016WLJH32), the Fundamental Research Funds of Shandong University (No. 2017JC006), Key Project of NSFC for International Cooperation (No. 81420108027), the Natural Science Foundation of Shandong Province (No. ZR2016HB26), and the Key research and development project of Shandong Province (No. 2017CXGC1401). All figures showing binding modes were generated using PyMol (www.pymol.org).
| Abbreviations Used | |
| AChE | acetylcholinesterase |
| ARMs | antibody-recruiting molecules |
| BSAA | broad-spectrum antiviral agents |
| CNS | central nervous system |
| CuAAC | copper(I)-catalyzed azide–alkyne [3 + 2] dipolar cycloaddition |
| DCC | dynamic combinatorial chemistry |
| DEL | DNA-encoded chemical library |
| DOS | diversity-oriented synthesis |
| DPM | drug profile matching |
| EPIs | efflux pump inhibitors |
| FDA | Food and Drug Administration |
| FMS | (2-sulfo)-9-fluorenylmethoxycarbonyl |
| GAT1 | γ-aminobutyric acid transporter 1 |
| HAS | human serum albumin |
| HDAC | histone deacetylase |
| Hh | hedgehog |
| HTS | high-throughput screen(ing) |
| LOPAC | library of pharmacologically active compounds |
| LSF | late-stage functionalization |
| MD | molecular dynamics |
| MLSD | multiple ligand simultaneous docking |
| MPO | multiparameter optimization |
| MS | mass spectrometry |
| NNRTIs | non-nucleoside reverse transcriptase inhibitors |
| Pf | Plasmodium falciparum |
| PROTACs | proteolysis-targeting chimeras |
| RT | reverse transcriptase |
| PXR | pregnane X receptor |
| SAR | structure–activity relationship |
| SPR | surface plasmon resonance |
| SKR | structure–kinetic relationship |
| TGS | target-guided synthesis |
| TOS | target-oriented synthesis |
| TTR | transthyretin |
| VEGFR2 | vascular endothelial growth receptor 2 |
References
ARTICLE SECTIONS
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], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVaju70%253D&md5=1bc058cfc32934b858a8c3519a8467bdTen Years of Medicinal Chemistry (2005-2014) in the Journal of Medicinal Chemistry: Country of Contributors, Topics, and Public-Private PartnershipsCostantino, Luca; Barlocco, DanielaJournal of Medicinal Chemistry (2016), 59 (16), 7352-7359CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This review analyzes the articles that have appeared during the past 10 years in the Journal of Medicinal Chem., the leading journal in the field of medicinal chem., to provide a picture of the changing trends in this research area. Our anal. involved the country of the corresponding author, assuming that he/she was the leader of the research group, the interaction between private and public sectors, and the research topics. This anal. provides information on the contributions to the journal of authors from each country and highlights the differences between the public and private sectors regarding the research topics pursued. Moreover, changes in the no. of articles that describe work on hits, leads, or clin. candidates during these years have been correlated with the affiliation of the contributors (public or private). An anal. of top-cited articles that have appeared in the journal has also been included. The data will provide the basis for understanding the evolution that is taking place in medicinal chem. - 2Aliagas, I.; Berger, R.; Goldberg, K.; Nishimura, R. T.; Reilly, J.; Richardson, P.; Richter, D.; Sherer, E. C. Sustainable practices in medicinal chemistry part 2: green by design. J. Med. Chem. 2017, 60, 5955– 5968, DOI: 10.1021/acs.jmedchem.6b01837[ACS Full Text], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsVygt7o%253D&md5=0b59ee948b306dc484dfd1d040af5f37Sustainable Practices in Medicinal Chemistry Part 2: Green by DesignAliagas, Ignacio; Berger, Raphaelle; Goldberg, Kristin; Nishimura, Rachel T.; Reilly, John; Richardson, Paul; Richter, Daniel; Sherer, Edward C.; Sparling, Brian A.; Bryan, Marian C.Journal of Medicinal Chemistry (2017), 60 (14), 5955-5968CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)With the development of ever-expanding synthetic methodologies, a medicinal chemist's toolkit continues to swell. However, with finite time and resources as well as a growing understanding of our field's environment impact, it is crit. to refine what can be made to what should be made. This review seeks to highlight multiple cheminformatic approaches in drug discovery that can influence and triage design and execution impacting the likelihood of rapidly generating high-value mols. in a more sustainable manner. This strategy gives chemists the tools to design and refine vast libraries, stress "druglikeness", and rapidly identify SAR trends. Project success, i.e., identification of a clin. candidate, is then reached faster with fewer mols. with the farther-reaching ramification of using fewer resources and generating less waste, thereby helping "green" our field.
- 3Bryan, M. C.; Dillon, B.; Hamann, L. G.; Hughes, G. J.; Kopach, M. E.; Peterson, E. A.; Pourashraf, M.; Raheem, I.; Richardson, P.; Richter, D.; Sneddon, H. F. Sustainable practices in medicinal chemistry: current state and future directions. J. Med. Chem. 2013, 56, 6007– 6021, DOI: 10.1021/jm400250p[ACS Full Text], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtVynurw%253D&md5=952b4e07a184f3c5e6c7bd94c793f4b3Sustainable Practices in Medicinal Chemistry: Current State and Future DirectionsBryan, Marian C.; Dillon, Barry; Hamann, Lawrence G.; Hughes, Gregory J.; Kopach, Michael E.; Peterson, Emily A.; Pourashraf, Mehrnaz; Raheem, Izzat; Richardson, Paul; Richter, Daniel; Sneddon, Helen F.Journal of Medicinal Chemistry (2013), 56 (15), 6007-6021CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The medicinal chem. subgroup of the American Chem. Society's Green Chem. Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chem. with the aim of sharing best practices more widely and highlighting some potential future developments.
- 4Zheng, M.; Zhao, J.; Cui, C.; Fu, Z.; Li, X.; Liu, X.; Ding, X.; Tan, X.; Li, F.; Luo, X.; Chen, K.; Jiang, H. Computational chemical biology and drug design: facilitating protein structure, function, and modulation studies. Med. Res. Rev. 2018, 38, 914– 950, DOI: 10.1002/med.21483[Crossref], [PubMed], [CAS], Google Scholar4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MzpslSktA%253D%253D&md5=fbf177fe25bae6e8d288dc6caf88b9b2Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studiesZheng Mingyue; Zhao Jihui; Cui Chen; Fu Zunyun; Li Xutong; Liu Xiaohong; Ding Xiaoyu; Tan Xiaoqin; Li Fei; Luo Xiaomin; Chen Kaixian; Jiang Hualiang; Liu Xiaohong; Chen Kaixian; Li FeiMedicinal research reviews (2018), 38 (3), 914-950 ISSN:.Over the past quarter of a century, there has been rapid development in structural biology, which now can provide solid evidence for understanding the functions of proteins. Concurrently, computational approaches with particular relevance to the chemical biology and drug design (CBDD) field have also incrementally and steadily improved. Today, these methods help elucidate detailed working mechanisms and accelerate the discovery of new chemical modulators of proteins. In recent years, integrating computational simulations and predictions with experimental validation has allowed for more effective explorations of the structure, function and modulation of important therapeutic targets. In this review, we summarize the main advancements in computational methodology development, which are then illustrated by several successful applications in CBDD. Finally, we conclude with a discussion of the current major challenges and future directions in the field.
- 5Zhan, P.; Itoh, Y.; Suzuki, T.; Liu, X. Strategies for the discovery of target-specific or isoform-selective modulators. J. Med. Chem. 2015, 58, 7611– 7633, DOI: 10.1021/acs.jmedchem.5b00229[ACS Full Text], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVans7rK&md5=2fdffce4f0c8c57a266468dcb8a901aeStrategies for the Discovery of Target-Specific or Isoform-Selective ModulatorsZhan, Peng; Itoh, Yukihiro; Suzuki, Takayoshi; Liu, XinyongJournal of Medicinal Chemistry (2015), 58 (19), 7611-7633CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Currently, the creation of class- and isoform-selective modulators of biol. important targets is a particularly challenging problem because different isoforms within a protein family often show striking similarity in spatial quaternary structure, esp. at the catalytic sites or binding pockets. Therefore, an understanding of both the precise three-dimensional structure of the target protein and the mechanisms of action of modulators is important for developing more effective and selective agents. In this Perspective, the authors discuss currently available rational design strategies for obtaining class- and isoform-selective inhibitors and the authors illustrate these strategies with the aid of specific examples from the recent literature. The strategies covered include: (1) target-derived (-dependent) de novo drug discovery methodologies, and (2) follow-on derivatization approaches from initially identified active mols. (hit-to-lead and lead-to-candidate efforts). The authors also comment on prospects for further development and integration of strategies to achieve target-specific or isoform-selective inhibition.
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- 7Young, R. J.; Leeson, P. D. Mapping the efficiency and physicochemical trajectories of successful optimizations. J. Med. Chem. 2018, 61, 6421– 6467, DOI: 10.1021/acs.jmedchem.8b00180[ACS Full Text], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntVCmu7Y%253D&md5=f040ef02d161e070bb5021fde1585e66Mapping the Efficiency and Physicochemical Trajectories of Successful OptimizationsYoung, Robert J.; Leeson, Paul D.Journal of Medicinal Chemistry (2018), 61 (15), 6421-6467CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The practices and tactics employed in successful optimizations are examd., judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technol.) and types of mols., including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful mols. are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks.
- 8Breckenridge, A.; Jacob, R. Overcoming the legal and regulatory barriers to drug repurposing. Nat. Rev. Drug Discovery 2018, 18, 1– 2, DOI: 10.1038/nrd.2018.92
- 9Pushpakom, S.; Iorio, F.; Eyers, P. A.; Escott, K. J.; Hopper, S.; Wells, A.; Doig, A.; Guilliams, T.; Latimer, J.; McNamee, C.; Norris, A.; Sanseau, P.; Cavalla, D.; Pirmohamed, M. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discovery 2018, 18, 41, DOI: 10.1038/nrd.2018.168
- 10Novac, N. Challenges and opportunities of drug repositioning. Trends Pharmacol. Sci. 2013, 34, 267– 272, DOI: 10.1016/j.tips.2013.03.004[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlvVChtL8%253D&md5=bc8f2269a723242c9cdc527c8d27b7f1Challenges and opportunities of drug repositioningNovac, NataliaTrends in Pharmacological Sciences (2013), 34 (5), 267-272CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)Drug repositioning is an innovation stream of pharmaceutical development that offers advantages for drug developers along with safer medicines for patients. Several drugs have been successfully repositioned to a new indication, with the most prominent of them being viagra and thalidomide, which have generated historically high revenues. In line with these developments, most of the recent articles and reviews on repositioning are focused on success stories, leaving behind the challenges that repositioned compds. have on the way to the clinic. Here, I analyze repositioning as a business opportunity for pharmaceutical companies, weighing both challenges and opportunities of repositioning. In addn., I suggest extended profiling as a lower-risk cost-effective repositioning model for pharmaceutical companies and elucidate the novel collaborative business opportunities that help to realize repositioning of shelved and marketed compds.
- 11Madrid, P. B.; Chopra, S.; Manger, I. D.; Gilfillan, L.; Keepers, T. R.; Shurtleff, A. C.; Green, C. E.; Iyer, L. V.; Dilks, H. H.; Davey, R. A.; Kolokoltsov, A. A.; Carrion, R., Jr.; Patterson, J. L.; Bavari, S.; Panchal, R. G.; Warren, T. K.; Wells, J. B.; Moos, W. H.; Burke, R. L.; Tanga, M. J. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One 2013, 8, e60579, DOI: 10.1371/journal.pone.0060579[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtlSgsrc%253D&md5=9041e9a699494765f27c68a9fcb8144eA systematic screen of FDA-approved drugs for inhibitors of biological threat agentsMadrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Hutcheson Dilks, Holli; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo, Jr.; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.PLoS One (2013), 8 (4), e60579CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The rapid development of effective medical countermeasures against potential biol. threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufg. and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. A large systematic effort to det. whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biol. threat pathogens, which were validated in secondary assays. As expected, antibiotic compds. were highly active against bacterial agents, but we did not identify any non-antibiotic compds. with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compds. in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compd. identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.
- 12Ashburn, T. T.; Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discovery 2004, 3, 673– 683, DOI: 10.1038/nrd1468[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVOhtL8%253D&md5=0145c02423ab81ace6e3b3d92585ccccDrug repositioning: identifying and developing new uses for existing drugsAshburn, Ted T.; Thor, Karl B.Nature Reviews Drug Discovery (2004), 3 (8), 673-683CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of prodn. to biotechnol. companies. More and more companies are scanning the existing pharmacopeia for repositioning candidates, and the no. of repositioning success stories is increasing.
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- 14Hayashi, T.; Jean, M.; Huang, H.; Simpson, S.; Santoso, N. G.; Zhu, J. Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription. Antiviral Res. 2017, 146, 76– 85, DOI: 10.1016/j.antiviral.2017.08.013[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtl2nsrzP&md5=3310d7e39f4e907dd32f1a1c39add801Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcriptionHayashi, Tsuyoshi; Jean, Maxime; Huang, Huachao; Simpson, Sydney; Santoso, Netty G.; Zhu, JianAntiviral Research (2017), 146 (), 76-85CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged "block and lock" approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clin. use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compd. library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.
- 15(a) Ren, J.; Zhao, Y.; Fry, E. E.; Stuart, D. I. Target identification and mode of action of four chemically divergent drugs against ebolavirus infection. J. Med. Chem. 2018, 61, 724– 733, DOI: 10.1021/acs.jmedchem.7b01249[ACS Full Text.], [CAS], Google Scholar15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVaksLjN&md5=682cf8a4441bc9b04ccdaf0488632e09Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus InfectionRen, Jingshan; Zhao, Yuguang; Fry, Elizabeth E.; Stuart, David I.Journal of Medicinal Chemistry (2018), 61 (3), 724-733CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we show that four chem. divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compds. The binding consts. (Kd) detd. by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities detd. by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.(b) Zhao, Y.; Ren, J.; Harlos, K.; Jones, D. M.; Zeltina, A.; Bowden, T. A.; Padilla-Parra, S.; Fry, E. E.; Stuart, D. I. Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 2016, 535, 169– 172, DOI: 10.1038/nature18615[Crossref], [PubMed], [CAS], Google Scholar.15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVOns7nF&md5=eceb89304e78acaf10097b333fb37478Toremifene interacts with and destabilizes the Ebola virus glycoproteinZhao, Yuguang; Ren, Jingshan; Harlos, Karl; Jones, Daniel M.; Zeltina, Antra; Bowden, Thomas A.; Padilla-Parra, Sergi; Fry, Elizabeth E.; Stuart, David I.Nature (London, United Kingdom) (2016), 535 (7610), 169-172CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here the authors report the first, to the knowledge, unliganded structure of EBOV GP, and high-resoln. complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resoln. apo structure gives a more complete and accurate picture of the mol., and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equiv. tunnels from the other monomers of the trimer at the three-fold axis. Protein-drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14° decrease in the protein melting temp. after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.(c) Zhao, Y.; Ren, J.; Fry, E. E.; Xiao, J.; Townsend, A. R.; Stuart, D. I. Structures of Ebola virus glycoprotein complexes with tricyclic antidepressant and antipsychotic drugs. J. Med. Chem. 2018, 61, 4938– 4945, DOI: 10.1021/acs.jmedchem.8b00350[ACS Full Text], [CAS], Google Scholar15chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12htr0%253D&md5=49278d793b6fc24ad6ad4d8a67170c4eStructures of Ebola Virus Glycoprotein Complexes with Tricyclic Antidepressant and Antipsychotic DrugsZhao, Yuguang; Ren, Jingshan; Fry, Elizabeth E.; Xiao, Julia; Townsend, Alain R.; Stuart, David I.Journal of Medicinal Chemistry (2018), 61 (11), 4938-4945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A large no. of Food and Drug Administration (FDA)-approved drugs have been found to inhibit the cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacol. targets, their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA-approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that antidepressants imipramine and clomipramine and antipsychotic drug thioridazine also directly interact with EBOV GP and det. the mode of interaction by crystallog. anal. of the complexes. The compds. bind within the same pocket as obsd. for other, chem. divergent complexes but with different binding modes. These details should be of value for the development of potent EBOV inhibitors.
- 16Zhang, L.; Wei, T. T.; Li, Y.; Li, J.; Fan, Y.; Huang, F. Q.; Cai, Y. Y.; Ma, G.; Liu, J. F.; Chen, Q. Q.; Wang, S. L.; Li, H.; Alolga, R. N.; Liu, B.; Zhao, D. S.; Shen, J. H.; Wang, X. M.; Zhu, W.; Li, P.; Qi, L. W. Functional metabolomics characterizes a key role for N-acetylneuraminic acid in coronary artery diseases. Circulation 2018, 137, 1374– 1390, DOI: 10.1161/CIRCULATIONAHA.117.031139[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvVKlt74%253D&md5=edff9fe687a87a1bace78c3b1c247217Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery DiseasesZhang, Lei; Wei, Ting-Ting; Li, Yong; Li, Jing; Fan, Yong; Huang, Feng-Qing; Cai, Yuan-Yuan; Ma, Gaoxiang; Liu, Jin-Feng; Chen, Qian-Qian; Wang, Shi-Lei; Li, Honglin; Alolga, Raphael N.; Liu, Baolin; Zhao, Dong-Sheng; Shen, Jian-Hua; Wang, Xiang-Ming; Zhu, Wei; Li, Ping; Qi, Lian-WenCirculation (2018), 137 (13), 1374-1390CODEN: CIRCAZ; ISSN:0009-7322. (Lippincott Williams & Wilkins)Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Methods: A cohort of 2324 patients who underwent coronary angiog. from 4 independent centers was studied. A combination of ultra-performance liq. chromatog. and quadrupole time-of-flight mass spectrometry in the neg. ion mode was used for untargeted anal. of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liq. chromatog.-mass spectrometry-based approach using isotope-labeled std. addn. was subsequently performed for targeted anal. of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. Results: We identified a total of 36 differential metabolites, 35 of which were confirmed with ref. compds. Elevation of Neu5Ac was obsd. in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-assocd. coiled-coil contg. protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation-induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacol. inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Conclusions: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
- 17Urquiza, P.; Laín, A.; Sanz-Parra, A.; Moreno, J.; Bernardo-Seisdedos, G.; Dubus, P.; González, E.; Gutiérrez-de-Juan, V.; García, S.; Eraña, H.; San Juan, I.; Macías, I.; Ben Bdira, F.; Pluta, P.; Ortega, G.; Oyarzábal, J.; González-Muñiz, R.; Rodríguez-Cuesta, J.; Anguita, J.; Díez, E.; Blouin, J. M.; de Verneuil, H.; Mato, J. M.; Richard, E.; Falcón-Pérez, J. M.; Castilla, J.; Millet, O. Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria. Sci. Transl. Med. 2018, 10, eaat7467, DOI: 10.1126/scitranslmed.aat7467
- 18Gwag, T.; Meng, Z.; Sui, Y.; Helsley, R. N.; Park, S. H.; Wang, S.; Greenberg, R. N.; Zhou, C. Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis. J. Hepatol. 2019, 70, 930, DOI: 10.1016/j.jhep.2018.12.038[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjt1Sqt74%253D&md5=623f1c1280d15072aa15930c5d1d2c13Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosisGwag, Taesik; Meng, Zhaojie; Sui, Yipeng; Helsley, Robert N.; Park, Se-Hyung; Wang, Shuxia; Greenberg, Richard N.; Zhou, ChangchengJournal of Hepatology (2019), 70 (5), 930-940CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)The most prescribed non-nucleoside reverse transcriptase inhibitor, efavirenz, has been assocd. with elevated risk of dyslipidemia and hepatic steatosis in HIV-infected patients but the underlying mechanisms remain elusive. Herein, we investigated the role of pregnane X receptor (PXR) in mediating the adverse effects of efavirenz on lipid homeostasis.Cell-based reporter assays, primary cell culture, and multiple mouse models including conditional knockout and humanized mice were combined to study the impact of efavirenz on PXR activities and lipid homeostasis in vitro and in vivo. A novel liver-specific Pxr knockout mouse model was also generated to det. the contribution of hepatic PXR signaling to efavirenz-elicited dyslipidemia and hepatic steatosis.We found that efavirenz is a potent PXR-selective agonist that can efficiently activate PXR and induce its target gene expression in vitro and in vivo. Treatment with efavirenz-induced hypercholesterolemia and hepatic steatosis in mice but deficiency of hepatic PXR abolished these adverse effects. Interestingly, efavirenz-mediated PXR activation regulated the expression of several key hepatic lipogenic genes including fatty acid transporter CD36 and cholesterol biosynthesis enzyme squalene epoxidase (SQLE), leading to increased lipid uptake and cholesterol biosynthesis in hepatic cells. While CD36 is a known PXR target gene, we identified a DR-2-type of PXR-response element in the SQLE promoter and established SQLE as a direct transcriptional target of PXR. Since PXR exhibits considerable differences in its pharmacol. across species, we also confirmed these findings in PXR-humanized mice and human primary hepatocytes.The widely prescribed antiretroviral drug efavirenz induces hypercholesterolemia and hepatic steatosis by activating PXR signaling. Activation of PXR should be taken into consideration for patients undergoing long-term treatment with PXR agonistic antiretroviral drugs.Efavirenz is widely prescribed for HIV-infected patients but has some side effects. It can increase lipid levels in patients' blood and liver. Here we show that efavirenz can activate a unique liver protein called PXR which mediates the adverse effects of efavirenz on lipid levels in mouse models.
- 19Gkountela, S.; Castro-Giner, F.; Szczerba, B. M.; Vetter, M.; Landin, J.; Scherrer, R.; Krol, I.; Scheidmann, M. C.; Beisel, C.; Stirnimann, C. U.; Kurzeder, C.; Heinzelmann-Schwarz, V.; Rochlitz, C.; Weber, W. P.; Aceto, N. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell 2019, 176, 98– 112, DOI: 10.1016/j.cell.2018.11.046[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXovFyqtw%253D%253D&md5=5a284c121841c562245da2948b8a4dedCirculating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis SeedingGkountela, Sofia; Castro-Giner, Francesc; Szczerba, Barbara Maria; Vetter, Marcus; Landin, Julia; Scherrer, Ramona; Krol, Ilona; Scheidmann, Manuel C.; Beisel, Christian; Stirnimann, Christian U.; Kurzeder, Christian; Heinzelmann-Schwarz, Viola; Rochlitz, Christoph; Weber, Walter Paul; Aceto, NicolaCell (Cambridge, MA, United States) (2019), 176 (1-2), 98-112.e14CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biol. features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-assocd. transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biol. Among 2,486 FDA-approved compds., we identify Na+/K+ ATPase inhibitors that enable the dissocn. of CTC clusters into single cells, leading to DNA methylation remodeling at crit. sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compds. to suppress the spread of cancer.
- 20Marrugal-Lorenzo, J. A.; Serna-Gallego, A.; Berastegui-Cabrera, J.; Pachón, J.; Sánchez-Céspedes, J. Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections. Sci. Rep. 2019, 9, 17, DOI: 10.1038/s41598-018-37290-3[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnpsl2gtQ%253D%253D&md5=39abad14b67924960bbec0203507c94bRepositioning salicylanilide anthelmintic drugs to treat adenovirus infectionsMarrugal-Lorenzo Jose A; Serna-Gallego Ana; Berastegui-Cabrera Judith; Pachon Jeronimo; Sanchez-Cespedes Javier; Pachon Jeronimo; Sanchez-Cespedes JavierScientific reports (2019), 9 (1), 17 ISSN:.The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia.
- 21Liu, Z.; Fang, H.; Reagan, K.; Xu, X.; Mendrick, D. L.; Slikker, W., Jr.; Tong, W. In silico drug repositioning: what we need to know. Drug Discovery Today 2013, 18, 110– 115, DOI: 10.1016/j.drudis.2012.08.005[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGnsL3J&md5=3a5c533b306e3fed00b49285efff3a33In silico drug repositioning - what we need to knowLiu, Zhichao; Fang, Hong; Reagan, Kelly; Xu, Xiaowei; Mendrick, Donna L.; Slikker, William; Tong, WeidaDrug Discovery Today (2013), 18 (3-4), 110-115CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs. Recent research has shown that bioinformatics-based approaches have the potential to offer systematic insights into the complex relationships among drugs, targets and diseases necessary for successful repositioning. In this article, we propose the key bioinformatics steps essential for discovering valuable repositioning methods. The proposed steps (repurposing with a purpose, repurposing with a strategy and repurposing with confidence) are aimed at providing a repurposing pipeline, with particular focus on the proposed Drugs of New Indications (DNI) database, which can be used alongside currently available resources to improve in silico drug repositioning.
- 22Haupt, V. J.; Schroeder, M. Old friends in new guise: repositioning of known drugs with structural bioinformatics. Briefings Bioinf. 2011, 12, 312– 326, DOI: 10.1093/bib/bbr011[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptl2jsrc%253D&md5=e50e0f4752302d91263af4803ef0f14dOld friends in new guise: repositioning of known drugs with structural bioinformaticsHaupt, V. Joachim; Schroeder, MichaelBriefings in Bioinformatics (2011), 12 (4), 312-326CODEN: BBIMFX; ISSN:1467-5463. (Oxford University Press)A review. Developing a drug de novo is a laborious and costly endeavor. Thus, the repositioning of already approved drugs for the treatment of new diseases is promising and valuable. One computational approach to repositioning exploits the structural similarity of binding sites of known and new targets. Here, we review computational methods to represent and align binding sites. We review available tools, present success stories and discuss limits of the approach.
- 23McClure, R. A.; Williams, J. D. Impact of mass spectrometry-based technologies and strategies on chemoproteomics as a tool for drug discovery. ACS Med. Chem. Lett. 2018, 9, 785– 791, DOI: 10.1021/acsmedchemlett.8b00181[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Kns7fO&md5=2db5a5a100646e41ac01bef8318bc7e4Impact of Mass Spectrometry-Based Technologies and Strategies on Chemoproteomics as a Tool for Drug DiscoveryMcClure, Ryan A.; Williams, Jon D.ACS Medicinal Chemistry Letters (2018), 9 (8), 785-791CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Chemoproteomics is an invaluable tool to discover protein targets from phenotypic assays and to understand on- and off-target engagement of potential therapeutic compds. Highlighted in this technol. perspective is our view on how improvements in mass spectrometry (MS)-based proteomics technol. have dramatically impacted chemoproteomics. Improvements in sample prepn., MS instrumentation, data acquisition, and quantification strategies have enabled medicinal chemists, chem. biologists, and mass spectrometrists to develop new chemoproteomic expts. and improve existing methods. As a result of improvements in MS, we will detail how bead-based affinity capture and activity-based proteome profiling methods have been reduced from multiple LC-MS runs for samples and controls down to a single LC-MS run each for sample and control. With improvements in scan duty cycle and sensitivity, sufficient depth of proteome coverage can be obtained for capture-free methods, which do not utilize an enrichment step.
- 24Lim, R. K.; Lin, Q. Photoinducible bioorthogonal chemistry: a spatiotemporally controllable tool to visualize and perturb proteins in live cells. Acc. Chem. Res. 2011, 44, 828– 839, DOI: 10.1021/ar200021p[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtlylt70%253D&md5=454ee044eca81c414f5f72118012ad28Photoinducible Bioorthogonal Chemistry: A Spatiotemporally Controllable Tool to Visualize and Perturb Proteins in Live CellsLim, Reyna K. V.; Lin, QingAccounts of Chemical Research (2011), 44 (9), 828-839CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Visualization in biol. has been greatly facilitated by the use of fluorescent proteins as in-cell probes. The genes coding for these wavelength-tunable proteins can be readily fused with the DNA coding for a protein of interest, which enables direct monitoring of natural proteins in real time inside living cells. Despite their success, however, fluorescent proteins have limitations that have only begun to be addressed in the past decade through the development of bioorthogonal chem. In this approach, a very small bioorthogonal tag is embedded within the basic building blocks of the cell, and then a variety of external mols. can be selectively conjugated to these pretagged biomols. The result is a veritable palette of biophys. probes for the researcher to choose from. In this Account, the authors review their progress in developing a photoinducible, bioorthogonal tetrazole-alkene cycloaddn. reaction ("photoclick chem.") and applying it to probe protein dynamics and function in live cells. The work described here summarizes the synthesis, structure, and reactivity studies of tetrazoles, including their optimization for applications in biol. Building on key insights from earlier reports, the authors' initial studies of the reaction have revealed full water compatibility, high photoactivation quantum yield, tunable photoactivation wavelength, and broad substrate scope; an added benefit is the formation of fluorescent cycloadducts. Subsequent studies have shown fast reaction kinetics (up to 11.0 M-1 s-1), with the rate depending on the HOMO energy of the nitrile imine dipole as well as the LUMO energy of the alkene dipolarophile. Moreover, through the use of photocrystallog., the authors have obsd. that the photogenerated nitrile imine adopts a bent geometry in the solid state. This observation has led to the synthesis of reactive, macrocyclic tetrazoles that contain a short "bridge" between two flanking Ph rings. This photoclick chem. has been used to label proteins rapidly (within ∼1 min) both in vitro and in Escherichia coli. To create an effective interface with biol., the authors have identified both a metabolically incorporable alkene amino acid, homoallylglycine, and a genetically encodable tetrazole amino acid, p-(2-tetrazole)phenylalanine. The authors demonstrate the utility of these two moieties, resp., in spatiotemporally controlled imaging of newly synthesized proteins and in site-specific labeling of proteins. Addnl., the authors demonstrate the use of the photoclick chem. to perturb the localization of a fluorescent protein in mammalian cells.
- 25Head, S. A.; Liu, J. O. Identification of small molecule-binding proteins in a native cellular environment by live-cell photoaffinity labeling. J. Vis. Exp. 2016, 115, e54529, DOI: 10.3791/54529
- 26Hill, J. R.; Robertson, A. A. B. Fishing for drug targets: a focus on diazirine photoaffinity probe synthesis. J. Med. Chem. 2018, 61, 6945– 6963, DOI: 10.1021/acs.jmedchem.7b01561[ACS Full Text], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotFart7g%253D&md5=37266e26bdd6a2028dddffc3ead4390dFishing for Drug Targets: A Focus on Diazirine Photoaffinity Probe SynthesisHill, James R.; Robertson, Avril A. B.Journal of Medicinal Chemistry (2018), 61 (16), 6945-6963CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient mol. interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even been incorporated by cellular machinery into proteins. Embarking on the synthesis of customized PAPs, contg. either an aliph. or trifluoromethyl Ph diazirine, can be a considerable endeavor, particularly for medicinal chemists and chem. biologists new to the field. This review takes a synthetic focus, aiming to summarize available routes, propose new avenues, and illuminate recent advances in diazirine synthesis. Select examples of diazirine photoaffinity labeling applications have been included throughout to provide instructive definition of the advantages and limitations of the technol. while simultaneously highlighting how these reagents can be applied in a practical sense.
- 27Hu, Y.; Wassermann, A. M.; Lounkine, E.; Bajorath, J. Systematic analysis of public domain compound potency data identifies selective molecular scaffolds across druggable target families. J. Med. Chem. 2010, 53, 752– 758, DOI: 10.1021/jm9014229[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFekt7%252FL&md5=aaf07367ea08bc6f49e29e94ae9bb231Systematic Analysis of Public Domain Compound Potency Data Identifies Selective Molecular Scaffolds across Druggable Target FamiliesHu, Ye; Wassermann, Anne Mai; Lounkine, Eugen; Bajorath, JuergenJournal of Medicinal Chemistry (2010), 53 (2), 752-758CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mol. scaffolds that yield target family-selective compds. are of high interest in pharmaceutical research. There continues to be considerable debate in the field as to whether chemotypes with a priority selectivity for given target families and/or targets exist and how they might be identified. What do currently available data tell us. We present a systematic and comprehensive selectivity-centric anal. of public domain target-ligand interactions. More than 200 mol. scaffolds are identified in currently available active compds. that are selective for established target families. A subset of these scaffolds is found to produce compds. with high selectivity for individual targets among closely related ones. These scaffolds are currently underrepresented in approved drugs.
- 28Ma, D. L.; Chan, D. S.; Leung, C. H. Drug repositioning by structure-based virtual screening. Chem. Soc. Rev. 2013, 42, 2130– 2141, DOI: 10.1039/c2cs35357a[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1Grsbo%253D&md5=8f419390fe9ac04b6e63ec17d91df471Drug repositioning by structure-based virtual screeningMa, Dik-Lung; Chan, Daniel Shiu-Hin; Leung, Chung-HangChemical Society Reviews (2013), 42 (5), 2130-2141CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Approved drugs have favorable or validated pharmacokinetic properties and toxicol. profiles, and the repositioning of existing drugs for new indications can potentially avoid expensive costs assocd. with early-stage testing of the hit compds. In recent years, technol. advances in virtual screening methodologies have allowed medicinal chemists to rapidly screen drug libraries for therapeutic activity against new biomol. targets in a cost-effective manner. This review article outlines the basic principles and recent advances in structure-based virtual screening and highlights the powerful synergy of in silico techniques in drug repositioning as demonstrated in several recent reports.
- 29Giannopoulos, P. F.; Chiu, J.; Pratico, D. Learning impairments, memory deficits, and neuropathology in aged tau transgenic mice are dependent on leukotrienes biosynthesis: role of the cdk5 kinase pathway. Mol. Neurobiol. 2019, 56, 1211, DOI: 10.1007/s12035-018-1124-7[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSmtrzP&md5=9c3b36329819f656295c22f847de5889Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase PathwayGiannopoulos, Phillip F.; Chiu, Jian; Pratico, DomenicoMolecular Neurobiology (2019), 56 (2), 1211-1220CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathol. phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathol. have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 mo of age for 16 wk and then assessed in their functional and pathol. phenotype. Compared with baseline, we obsd. that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant redn. in tau phosphorylation and pathol., which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathol. phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.
- 30Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y. Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis. J. Med. Chem. 2017, 60, 1817– 1828, DOI: 10.1021/acs.jmedchem.6b01507[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtVWqurk%253D&md5=a94045bbbe5514eb48b1468b54cac0b5Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 BiosynthesisLu, Weiqiang; Yao, Xue; Ouyang, Ping; Dong, Ningning; Wu, Dang; Jiang, Xingwu; Wu, Zengrui; Zhang, Chen; Xu, Zhongyu; Tang, Yun; Zou, Shien; Liu, Mingyao; Li, Jian; Zeng, Minghua; Lin, Ping; Cheng, Feixiong; Huang, JinJournal of Medicinal Chemistry (2017), 60 (5), 1817-1828CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, the authors identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analog 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymic assay, thermofluor assay, and x-ray Crystallog. investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clin. safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were detd. in vivo. Collectively, 1 and 2 would provide promising agents with well-known clin. safety for potential treatment in patients with ALI and IPF via pharmacol. inhibiting LAT4H and blocking LTB4 biosynthesis.
- 31Iwata, M.; Hirose, L.; Kohara, H.; Liao, J.; Sawada, R.; Akiyoshi, S.; Tani, K.; Yamanishi, Y. Pathway-based drug repositioning for cancers: computational prediction and experimental validation. J. Med. Chem. 2018, 61, 9583– 9595, DOI: 10.1021/acs.jmedchem.8b01044[ACS Full Text], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVWit7fN&md5=ebdf14f917554fff73592cbb2e7c10f8Pathway-Based Drug Repositioning for Cancers: Computational Prediction and Experimental ValidationIwata, Michio; Hirose, Lisa; Kohara, Hiroshi; Liao, Jiyuan; Sawada, Ryusuke; Akiyoshi, Sayaka; Tani, Kenzaburo; Yamanishi, YoshihiroJournal of Medicinal Chemistry (2018), 61 (21), 9583-9595CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use mol. pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chem. induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and exptl. validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
- 32Mejía-Pedroza, R. A.; Espinal-Enríquez, J.; Hernández-Lemus, E. Pathway-based drug repositioning for breast cancer molecular subtypes. Front Pharmacol. 2018, 9, 905, DOI: 10.3389/fphar.2018.00905[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtVaqsrs%253D&md5=51adc21df40b93cac9c088583436f4c1Pathway-based drug repositioning for breast cancer molecular subtypesMejia-Pedroza, Raul A.; Espinal-Enriquez, Jesus; Hernandez-Lemus, EnriqueFrontiers in Pharmacology (2018), 9 (), 905/1-905/13CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)Breast cancer is a major public health problem which treatment needs new pharmacol. options. In the last decades, during the postgenomic era new theor. and technol. tools that give us novel and promising ways to address these problems have emerged. In this work, we integrate several tools that exploit disease-specific exptl. transcriptomic results in addn. to information from biol. and pharmacol. data bases obtaining a contextual prioritization of pathways and drugs in breast cancer subtypes. The usefulness of these results should be evaluated in terms of drug repurposing in each breast cancer mol. subtype therapy. In favor of breast cancer patients, this methodol. could be further developed to provide personalized treatment schemes. The latter are particularly needed in those breast cancer subtypes with limited therapeutic options or those who have developed resistance to the current pharmacol. schemes.
- 33Huang, C. H.; Chang, P. M.; Lin, Y. J.; Wang, C. H.; Huang, C. Y.; Ng, K. L. Drug repositioning discovery for early- and late-stage non-small-cell lung cancer. Biomed Res. Int. 2014, 2014, 193817, DOI: 10.1155/2014/193817[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7gsVWqtQ%253D%253D&md5=2e0c6fbc90b3ccac729ace9759901d72Drug repositioning discovery for early- and late-stage non-small-cell lung cancerHuang Chien-Hung; Lin Yong-Jie; Chang Peter Mu-Hsin; Wang Cheng-Hsu; Huang Chi-Ying F; Ng Ka-LokBioMed research international (2014), 2014 (), 193817 ISSN:.Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC) is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.
- 34Astolfi, A.; Felicetti, T.; Iraci, N.; Manfroni, G.; Massari, S.; Pietrella, D.; Tabarrini, O.; Kaatz, G. W.; Barreca, M. L.; Sabatini, S.; Cecchetti, V. Pharmacophore-based repositioning of approved drugs as novel staphylococcus aureus NorA efflux pump inhibitors. J. Med. Chem. 2017, 60, 1598– 1604, DOI: 10.1021/acs.jmedchem.6b01439[ACS Full Text], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFajsbY%253D&md5=6936777b99a9832f2582c22c9492bc1dPharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump InhibitorsAstolfi, Andrea; Felicetti, Tommaso; Iraci, Nunzio; Manfroni, Giuseppe; Massari, Serena; Pietrella, Donatella; Tabarrini, Oriana; Kaatz, Glenn W.; Barreca, Maria L.; Sabatini, Stefano; Cecchetti, ViolettaJournal of Medicinal Chemistry (2017), 60 (4), 1598-1604CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An intriguing opportunity to address antimicrobial resistance is represented by the inhibition of efflux pumps. Focusing on NorA, the most important efflux pump of Staphylococcus aureus, an efflux pump inhibitors (EPIs) library was used for ligand-based pharmacophore modeling studies. Exploiting the obtained models, an in silico drug repositioning approach allowed for the identification of novel and potent NorA EPIs.
- 35Fako, V. E.; Wu, X.; Pflug, B.; Liu, J. Y.; Zhang, J. T. Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase. J. Med. Chem. 2015, 58, 778– 784, DOI: 10.1021/jm501543u[ACS Full Text], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOhu7%252FN&md5=33e2aa65f5a5b4fd5f14df6e618982edRepositioning Proton Pump Inhibitors as Anticancer Drugs by Targeting the Thioesterase Domain of Human Fatty Acid SynthaseFako, Valerie E.; Wu, Xi; Pflug, Beth; Liu, Jing-Yuan; Zhang, Jian-TingJournal of Medicinal Chemistry (2015), 58 (2), 778-784CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clin. use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compds. may be acting on cancer cells.
- 36(a) Li, H.; Liu, A.; Zhao, Z.; Xu, Y.; Lin, J.; Jou, D.; Li, C. Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J. Med. Chem. 2011, 54, 5592– 5596, DOI: 10.1021/jm101330h[ACS Full Text.], [CAS], Google Scholar36ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFykurs%253D&md5=eab2abdff8c67119767b0c147920ad4cFragment-Based Drug Design and Drug Repositioning Using Multiple Ligand Simultaneous Docking (MLSD): Identifying Celecoxib and Template Compounds as Novel Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3)Li, Huameng; Liu, Aiguo; Zhao, Zhenjiang; Xu, Yufang; Lin, Jiayuh; Jou, David; Li, ChenglongJournal of Medicinal Chemistry (2011), 54 (15), 5592-5596CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors describe a novel method of drug discovery using MLSD and drug repositioning, with cancer target STAT3 being used as a test case. Multiple drug scaffolds were simultaneously docked into hot spots of STAT3 by MLSD, followed by tethering to generate virtual template compds. Similarity search of virtual hits on drug database identified celecoxib as a novel inhibitor of STAT3. Furthermore, the authors designed two novel lead inhibitors based on one of the lead templates and celecoxib.(b) Li, H.; Xiao, H.; Lin, L.; Jou, D.; Kumari, V.; Lin, J.; Li, C. Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J. Med. Chem. 2014, 57, 632– 641, DOI: 10.1021/jm401144z[ACS Full Text], [CAS], Google Scholar36bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ohtr8%253D&md5=a4f2887c2ad3a5dc97827e7a7499efe0Drug Design Targeting Protein-Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 InterfaceLi, Huameng; Xiao, Hui; Lin, Li; Jou, David; Kumari, Vandana; Lin, Jiayuh; Li, ChenglongJournal of Medicinal Chemistry (2014), 57 (3), 632-641CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The IL-6/GP130/STAT3 pathway is crit. for the progression of multiple types of cancers. The authors report the discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into hot spots of GP130 D1 domain by MLSD to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compds. Similarity searches of virtual hits on drug databases identified raloxifene and bazedoxifene as potential inhibitors of IL-6/GP130 interaction. In cancer cell assays both compds. bind to GP130 and demonstrated selective inhibition of IL-6 induced STAT3 phosphorylation and were significantly more potent than the previously reported natural product inhibitor MDL-A. The identified drugs represent a new class of lead compds. with piperidine, benzothiophene, and indole scaffolds to inhibit IL-6 induced homodimerization of GP130. Besides potential direct usage for clinic trials, the two compds. can also serve as lead compds. for optimization to speed the development of drugs selectively targeting the IL-6/GP130/STAT3 cancer signaling pathway.
- 37Vegner, L.; Peragovics, A.; Tombor, L.; Jelinek, B.; Czobor, P.; Bender, A.; Simon, Z.; Malnasi-Csizmadia, A. Experimental confirmation of new drug-target interactions predicted by drug profile matching. J. Med. Chem. 2013, 56, 8377– 8388, DOI: 10.1021/jm400813y[ACS Full Text], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFGrsr7I&md5=7790bed590d1d57b3a633ddf211ca5aaExperimental Confirmation of New Drug-Target Interactions Predicted by Drug Profile MatchingVegner, Laszlo; Peragovics, Agnes; Tombor, Laszlo; Jelinek, Balazs; Czobor, Pal; Bender, Andreas; Simon, Zoltan; Malnasi-Csizmadia, AndrasJournal of Medicinal Chemistry (2013), 56 (21), 8377-8388CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quant. predict the complete effect profiles of compds. via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature anal. as well as exptl. A total of 72% of the newly predicted and tested dopaminergic compds. were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, resp. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory consts. (Ki) were detd. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
- 38Huang, C. H.; Chang, P. M.; Hsu, C. W.; Huang, C. Y.; Ng, K. L. Drug repositioning for non-small cell lung cancer by using machine learning algorithms and topological graph theory. BMC Bioinformatics 2016, 17, S2, DOI: 10.1186/s12859-015-0845-0[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltFeksA%253D%253D&md5=43fc74bd2590159623167ed695a74accDrug repositioning for non-small cell lung cancer by using machine learning algorithms and topological graph theoryHuang, Chien-Hung; Chang, Peter Mu-Hsin; Hsu, Chia-Wei; Huang, Chi-Ying F.; Ng, Ka-LokBMC Bioinformatics (2016), 17 (Suppl.1), 2/1-2/14CODEN: BBMIC4; ISSN:1471-2105. (BioMed Central Ltd.)Background: Non-small cell lung cancer (NSCLC) is one of the leading causes of death globally, and research into NSCLC has been accumulating steadily over several years. Drug repositioning is the current trend in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development process of drugs, as well as reducing side effects. Results: This work integrates two approaches - machine learning algorithms and topol. parameter-based classification - to develop a novel pipeline of drug repositioning to analyze four lung cancer microarray datasets, enriched biol. processes, potential therapeutic drugs and targeted genes for NSCLC treatments. A total of 7 (8) and 11 (12) promising drugs (targeted genes) were discovered for treating early- and late-stage NSCLC, resp. The effectiveness of these drugs is supported by the literature, exptl. detd. in-vitro IC50 and clin. trials. This work provides better drug prediction accuracy than competitive research according to IC50 measurements. Conclusions: With the novel pipeline of drug repositioning, the discovery of enriched pathways and potential drugs related to NSCLC can provide insight into the key regulators of tumorigenesis and the treatment of NSCLC. Based on the verified effectiveness of the targeted drugs predicted by this pipeline, we suggest that our drug-finding pipeline is effective for repositioning drugs.
- 39Dakshanamurthy, S.; Issa, N. T.; Assefnia, S.; Seshasayee, A.; Peters, O. J.; Madhavan, S.; Uren, A.; Brown, M. L.; Byers, S. W. Predicting new indications for approved drugs using a proteochemometric method. J. Med. Chem. 2012, 55, 6832– 6848, DOI: 10.1021/jm300576q[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVWhtL3K&md5=a7f3c746f47ae9370aa0d9faccd1f1bdPredicting New Indications for Approved Drugs Using a Proteochemometric MethodDakshanamurthy, Sivanesan; Issa, Naiem T.; Assefnia, Shahin; Seshasayee, Ashwini; Peters, Oakland J.; Madhavan, Subha; Uren, Aykut; Brown, Milton L.; Byers, Stephen W.Journal of Medicinal Chemistry (2012), 55 (15), 6832-6848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chem. screening, transcriptome matching, or simple in silico ligand docking. We now describe a novel rapid computational proteochemometric method called "train, match, fit, streamline" (TMFS) to map new drug-target interaction space and predict new uses. The TMFS method combines shape, topol., and chem. signatures, including docking score and functional contact points of the ligand, to predict potential drug-target interactions with remarkable accuracy. Using the TMFS method, we performed extensive mol. fit computations on 3671 FDA approved drugs across 2335 human protein crystal structures. The TMFS method predicts drug-target assocns. with 91% accuracy for the majority of drugs. Over 58% of the known best ligands for each target were correctly predicted as top ranked, followed by 66%, 76%, 84%, and 91% for agents ranked in the top 10, 20, 30, and 40, resp., out of all 3671 drugs. Drugs ranked in the top 1-40 that have not been exptl. validated for a particular target now become candidates for repositioning. Furthermore, we used the TMFS method to discover that mebendazole, an antiparasitic with recently discovered and unexpected anticancer properties, has the structural potential to inhibit VEGFR2. We confirmed exptl. that mebendazole inhibits VEGFR2 kinase activity and angiogenesis at doses comparable with its known effects on hookworm. TMFS also predicted, and was confirmed with surface plasmon resonance, that di-Me celecoxib and the anti-inflammatory agent celecoxib can bind cadherin-11, an adhesion mol. important in rheumatoid arthritis and poor prognosis malignancies for which no targeted therapies exist. We anticipate that expanding our TMFS method to the >27 000 clin. active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets.
- 40Coley, C. W.; Green, W. H.; Jensen, K. F. Machine learning in computer-aided synthesis planning. Acc. Chem. Res. 2018, 51, 1281– 1289, DOI: 10.1021/acs.accounts.8b00087[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFKhsb0%253D&md5=a1ea72c55942f3c0f0a99ab080f96899Machine Learning in Computer-Aided Synthesis PlanningColey, Connor W.; Green, William H.; Jensen, Klavs F.Accounts of Chemical Research (2018), 51 (5), 1281-1289CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small mol. compds. The ideal CASP program would take a mol. structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chem. feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two crit. aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target mol. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing no. of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chem. reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of exptl. success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network-based approaches that we and others have developed for this forward prediction task that can be trained on previously published exptl. data. Machine learning and artificial intelligence have revolutionized a no. of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure-activity models in chem., it is only now that it is being successfully applied more broadly to org. synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large.
- 41Zhong, F.; Xing, J.; Li, X.; Liu, X.; Fu, Z.; Xiong, Z.; Lu, D.; Wu, X.; Zhao, J.; Tan, X.; Li, F.; Luo, X.; Li, Z.; Chen, K.; Zheng, M.; Jiang, H. Artificial intelligence in drug design. Sci. China: Life Sci. 2018, 61, 1191, DOI: 10.1007/s11427-018-9342-2[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7ivVemsw%253D%253D&md5=bc9be49e1b60b815eed9494cd7d174c5Artificial intelligence in drug designZhong Feisheng; Xing Jing; Li Xutong; Liu Xiaohong; Fu Zunyun; Xiong Zhaoping; Lu Dong; Wu Xiaolong; Zhao Jihui; Tan Xiaoqin; Li Fei; Luo Xiaomin; Chen Kaixian; Zheng Mingyue; Jiang Hualiang; Zhong Feisheng; Xing Jing; Li Xutong; Fu Zunyun; Lu Dong; Wu Xiaolong; Zhao Jihui; Tan Xiaoqin; Liu Xiaohong; Xiong Zhaoping; Chen Kaixian; Jiang Hualiang; Li Fei; Li ZhaojunScience China. Life sciences (2018), 61 (10), 1191-1204 ISSN:.Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology, the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials. Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence (AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening, activity scoring, quantitative structure-activity relationship (QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability, deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules, which will further promote the application of AI technologies in the field of drug design.
- 42Polamreddy, P.; Gattu, N. The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions. Drug Discovery Today 2019, 24, 789, DOI: 10.1016/j.drudis.2018.11.022[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crosVOjug%253D%253D&md5=c3fe65336ec6d598fd2f933d0174f6d6The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutionsPolamreddy Prasanthi; Gattu NanduDrug discovery today (2019), 24 (3), 789-795 ISSN:.As the name suggests, drug repurposing is a strategy to identify new therapeutic uses for marketed drugs, discontinued and/or shelved drugs, and drug candidates currently in clinical development. Although not a recent concept, drug repurposing has gained momentum over the past few years and several drugs have been successfully repurposed. Here, we summarize the drug repurposing landscape from 2012 to 2017, with a major focus on repurposed drugs, collaborative opportunities, and funding opportunities specific to drug repurposing projects. Along with success stories, we also highlight the challenges and limitations associated with drug repurposing.
- 43(a) Bartolini, S.; Mai, A.; Artico, M.; Paesano, N.; Rotili, D.; Spadafora, C.; Sbardella, G. 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones antagonize cell proliferation and induce cell differentiation by inhibiting (a nontelomeric) endogenous reverse transcriptase. J. Med. Chem. 2005, 48, 6776– 6778, DOI: 10.1021/jm0507330[ACS Full Text.], [CAS], Google Scholar43ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVGqsrrO&md5=bed817e48bba30e296dabc536e156b516-[1-(2,6-Difluorophenyl)ethyl]pyrimidinones Antagonize Cell Proliferation and Induce Cell Differentiation by Inhibiting (a Nontelomeric) Endogenous Reverse TranscriptaseBartolini, Sara; Mai, Antonello; Artico, Marino; Paesano, Nicola; Rotili, Dante; Spadafora, Corrado; Sbardella, GianlucaJournal of Medicinal Chemistry (2005), 48 (22), 6776-6778CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two 2,6-difluoro-DABO derivs. (MC 1047, 1, and MC 1220, 2, resp.) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compds. significantly reduced cell proliferation and facilitated the morphol. differentiation of cells. These results propose F2-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.(b) Sbardella, G.; Mai, A.; Bartolini, S.; Castellano, S.; Cirilli, R.; Rotili, D.; Milite, C.; Santoriello, M.; Orlando, S.; Sciamanna, I.; Serafino, A.; Lavia, P.; Spadafora, C. Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors. J. Med. Chem. 2011, 54, 5927– 5936, DOI: 10.1021/jm200734j[ACS Full Text], [CAS], Google Scholar43bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptlSmsb4%253D&md5=28a907965efda96d77ba50dbd69dd691Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase InhibitorsSbardella, Gianluca; Mai, Antonello; Bartolini, Sara; Castellano, Sabrina; Cirilli, Roberto; Rotili, Dante; Milite, Ciro; Santoriello, Marisabella; Orlando, Serena; Sciamanna, Ilaria; Serafino, Annalucia; Lavia, Patrizia; Spadafora, CorradoJournal of Medicinal Chemistry (2011), 54 (16), 5927-5936CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivs. (3a-h) belonging to the F2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compds., the most potent is 3g (SPV122), which also induces apoptosis in a cell-d.-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.
- 44Shahinas, D.; Liang, M.; Datti, A.; Pillai, D. R. A repurposing strategy identifies novel synergistic inhibitors of plasmodium falciparum heat shock protein 90. J. Med. Chem. 2010, 53, 3552– 3557, DOI: 10.1021/jm901796s[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFKjtLg%253D&md5=e71807df99016cdaab2d338080162f11A Repurposing Strategy Identifies Novel Synergistic Inhibitors of Plasmodium falciparum Heat Shock Protein 90Shahinas, Dea; Liang, Michael; Datti, Alessandro; Pillai, Dylan R.Journal of Medicinal Chemistry (2010), 53 (9), 3552-3557CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Malaria is responsible for 3 million deaths annually. Antimalarial drug resistance is widespread, and few novel, well-defined targets exist. A robotic high throughput screen (HTS) was performed using 4000 small mols. from a natural compd. (Spectrum), pharmacol. active (Lopac), and Food and Drug Administration (FDA) approved drug library (Prestwick) for competitive inhibition of the ATP-binding (GHKL) domain of Plasmodium falciparum (Pf) Hsp90, a highly conserved chaperone. Hits were further screened for specificity based on differential inhibition of PfHsp90 in comparison to human (Hs) Hsp90. PfHsp90-specific inhibitors showed 50% inhibitory concns. (IC50) in the nanomolar range when tested using a cell-based antimalarial validation assay. Three hits, identified as selective PfHsp90 inhibitors in the HTS, also demonstrated synergistic activity in the presence of the known antimalarial drug chloroquine. These data support PfHsp90 as a specific antimalarial target with potential for synergy with known antimalarials.
- 45Deeks, E. D. Lesinurad: a review in hyperuricaemia of gout. Drugs Aging 2017, 34, 401– 410, DOI: 10.1007/s40266-017-0461-y[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmsFGjs7w%253D&md5=82a18964b609bc9da3909f715fd35c67Lesinurad: A Review in Hyperuricaemia of GoutDeeks, Emma D.Drugs & Aging (2017), 34 (5), 401-410CODEN: DRAGE6; ISSN:1170-229X. (Springer International Publishing AG)Lesinurad (Zurampic) is an oral selective inhibitor of the URAT1 and OAT4 uric acid (UA) transporters of the kidney, via which it inhibits UA reabsorption and thus increases renal UA excretion and lowers serum UA (sUA) levels. Lesinurad 200 mg once daily is indicated for use in combination with a xanthine oxidase inhibitor (XOI) to treat hyperuricemia in adults with gout who have not achieved target sUA levels with an XOI alone. Approval was based on three 12-mo phase 3 trials that evaluated lesinurad in combination with allopurinol in adults with gout inadequately responsive to allopurinol (CLEAR 1 and 2) and in combination with febuxostat in adults with tophaceous gout (CRYSTAL). The target sUA level of <6 mg/dL at 6 mo (primary endpoint) was achieved by significantly more lesinurad plus allopurinol than placebo plus allopurinol recipients in the CLEAR trials. In CRYSTAL (which enrolled patients regardless of prior XOI experience, and included 3 wk of febuxostat before randomization), the proportion of patients who achieved an sUA target of <5 mg/dL did not reach statistical significance between lesinurad plus febuxostat and placebo plus febuxostat at 6 mo (primary endpoint), although significantly favored the lesinurad plus febuxostat group at 12 mo. Notably, the sUA target of <5 mg/dL at 6 mo was met with lesinurad plus febuxostat in the CRYSTAL subgroup that had uncontrolled hyperuricemia at baseline, despite having received febuxostat pre-randomization. Lesinurad plus XOI regimens were generally not assocd. with improvements in flares and tophi in these trials, although clin. benefit became more apparent in 12-mo extension studies; the regimens were also generally well tolerated. Thus, lesinurad, in combination with an XOI, is an emerging option for the treatment of hyperuricemia in adults with gout who have not achieved target sUA levels with an XOI alone.
- 46Hoy, S. M. Lesinurad: first global approval. Drugs 2016, 76, 509– 516, DOI: 10.1007/s40265-016-0550-y[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisFGrsr4%253D&md5=adff81ec4e67f65711573f15444765c8Lesinurad: First Global ApprovalHoy, Sheridan M.Drugs (2016), 76 (4), 509-516CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Lesinurad (ZURAMPIC) is an oral urate-anion exchanger transporter 1 (URAT1) inhibitor developed by Ardea Biosciences (a subsidiary of AstraZeneca) for the treatment of hyperuricemia assocd. with gout. It reduces serum uric acid (sUA) levels by inhibiting the function of the transporter proteins (URAT1 and org. anion transporter 4) involved in uric acid reabsorption in the kidney. In Dec. 2015, lesinurad was approved in the USA as combination therapy with a xanthine oxidase inhibitor for the treatment of hyperuricemia assocd. with gout in patients who have not achieved sUA target levels with a xanthine oxidase inhibitor alone. Lesinurad has also received a pos. opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use for this indication and is in phase III development as a combination therapy in several other countries. This article summarizes the milestones in the development of lesinurad leading to this first approval for hyperuricemia assocd. with gout.
- 47Pace, J. R.; DeBerardinis, A. M.; Sail, V.; Tacheva-Grigorova, S. K.; Chan, K. A.; Tran, R.; Raccuia, D. S.; Wechsler-Reya, R. J.; Hadden, M. K. Repurposing the clinically efficacious antifungal agent itraconazole as an anticancer chemotherapeutic. J. Med. Chem. 2016, 59, 3635– 3649, DOI: 10.1021/acs.jmedchem.5b01718[ACS Full Text], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVOrt74%253D&md5=c7132006ac3bc3a6d74828d1aa3b0702Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer ChemotherapeuticPace, Jennifer R.; DeBerardinis, Albert M.; Sail, Vibhavari; Tacheva-Grigorova, Silvia K.; Chan, Kelly A.; Tran, Raymond; Raccuia, Daniel S.; Wechsler-Reya, Robert J.; Hadden, M. KyleJournal of Medicinal Chemistry (2016), 59 (8), 3635-3649CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogs for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochem. defined des-triazole ITZ analogs also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- 48(a) Shi, W.; Nacev, B. A.; Aftab, B. T.; Head, S.; Rudin, C. M.; Liu, J. O. Itraconazole side chain analogues: structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling. J. Med. Chem. 2011, 54, 7363– 7674, DOI: 10.1021/jm200944b[ACS Full Text.], [CAS], Google Scholar48ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Onsb7M&md5=69caea82df24ba45e31c48dd326f8c5bItraconazole Side Chain Analogues: Structure-Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog SignalingShi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O.Journal of Medicinal Chemistry (2011), 54 (20), 7363-7374CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogs of itraconazole with greater potency and to understand the structure-activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogs were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this anal., we have identified analogs with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR anal. of these activities revealed that potent activity of the analogs against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in compn. with branching at the α or β position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-Bu side chain can lead to enhancement of the biol. activity of itraconazole.(b) Li, Y.; Pasunooti, K. K.; Li, R. J.; Liu, W.; Head, S. A.; Shi, W. Q.; Liu, J. O. Novel tetrazole-containing analogs of itraconazole as potent anti-angiogenic agents with reduced CYP3A4 inhibition. J. Med. Chem. 2018, 61, 11158, DOI: 10.1021/acs.jmedchem.8b01252[ACS Full Text], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCmsb7J&md5=6337b8db0718df19a55a54329badca15Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 InhibitionLi, Yingjun; Pasunooti, Kalyan Kumar; Li, Ruo-Jing; Liu, Wukun; Head, Sarah A.; Shi, Wei Q.; Liu, Jun O.Journal of Medicinal Chemistry (2018), 61 (24), 11158-11168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clin. studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P 450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivs. in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogs, I with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, I induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that I is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
- 49Thompson, A. M.; O’Connor, P. D.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin, D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases: structure-activity studies on a preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2016, 59, 2530– 2550, DOI: 10.1021/acs.jmedchem.5b01699[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmtbY%253D&md5=9eebc55cc434cc4dec0692bef5bbed98Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Blaser, Adrian; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Martin, Denis; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2016), 59 (6), 2530-2550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivs. were initially studied for tuberculosis within a backup program for the clin. trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Addnl. work was then conducted to delineate its essential structural features, aiming to improve soly. and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of Ph rings by pyridine. Several less lipophilic analogs displayed improved aq. soly., particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection,phenylpyridine deriv. I stood out, providing efficacy surpassing that of the original preclin. lead.
- 50Turk, S.; Merget, B.; Eid, S.; Fulle, S. From cancer to pain target by automated selectivity inversion of a clinical candidate. J. Med. Chem. 2018, 61, 4851– 4859, DOI: 10.1021/acs.jmedchem.8b00140[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hurc%253D&md5=8e29a51d656eb52a41d9abc6fc22ca59From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical CandidateTurk, Samo; Merget, Benjamin; Eid, Sameh; Fulle, SimoneJournal of Medicinal Chemistry (2018), 61 (11), 4851-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compds. in clin. trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-detg. features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compds. based on orthogonal methods grounded in computational chem. and machine learning. Eighteen high-ranking compds. were synthesized and exptl. tested. The top-ranked compd. has 10000-fold improved selectivity vs. AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
- 51Perlmutter, J. I.; Forbes, L. T.; Krysan, D. J.; Ebsworth-Mojica, K.; Colquhoun, J. M.; Wang, J. L.; Dunman, P. M.; Flaherty, D. P. Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus. J. Med. Chem. 2014, 57, 8540– 8562, DOI: 10.1021/jm5010682[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyjtb%252FI&md5=190dd3fd565b52b2d693a475c4cb62c1Repurposing the Antihistamine Terfenadine for Antimicrobial Activity against Staphylococcus aureusPerlmutter, Jessamyn I.; Forbes, Lauren T.; Krysan, Damian J.; Ebsworth-Mojica, Katherine; Colquhoun, Jennifer M.; Wang, Jenna L.; Dunman, Paul M.; Flaherty, Daniel P.Journal of Medicinal Chemistry (2014), 57 (20), 8540-8562CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-pos. bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogs with several modifications providing increased activity vs. S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compds. to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogs provide a novel structural class of antimicrobial compds. with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.
- 52Dilly, S.; Fotso Fotso, A.; Lejal, N.; Zedda, G.; Chebbo, M.; Rahman, F.; Companys, S.; Bertrand, H. C.; Vidic, J.; Noiray, M.; Alessi, M. C.; Tarus, B.; Quideau, S.; Riteau, B.; Slama-Schwok, A. From naproxen repurposing to naproxen analogues and their antiviral activity against influenza A virus. J. Med. Chem. 2018, 61, 7202– 7217, DOI: 10.1021/acs.jmedchem.8b00557[ACS Full Text], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGit7jI&md5=a3d21246bea09e82edd808d1e14a54eeFrom Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A VirusDilly, Sebastien; Fotso Fotso, Aurelien; Lejal, Nathalie; Zedda, Gloria; Chebbo, Mohamad; Rahman, Fryad; Companys, Simon; Bertrand, Helene C.; Vidic, Jasmina; Noiray, Magali; Alessi, Marie-Christine; Tarus, Bogdan; Quideau, Stephane; Riteau, Beatrice; Slama-Schwok, AnnyJournal of Medicinal Chemistry (2018), 61 (16), 7202-7217CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. The authors previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here the authors designed and synthesized two new series of naproxen analogs called derivs. 2, 3 (5-(4-aminophenoxy)-2-(6-methoxynaphthalen-2-yl)isophthalic acid), and 4 (4-(4-aminophenoxy)-2-(6-methoxynaphthalen-2-yl)isophthalic acid) targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Deriv. 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Deriv. 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivs. 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
- 53Mohiuddin, G.; Khan, K. M.; Salar, U.; Kanwal; Wadood, A.; Riaz, M.; Perveen, S. Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivatives. Bioorg. Chem. 2019, 83, 29– 46, DOI: 10.1016/j.bioorg.2018.10.021[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFeisrzN&md5=7577a5d8e6672125f32e3d4bd16fc6bfBiology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivativesMohiuddin, Ghulam; Khan, Khalid Mohammed; Salar, Uzma; Kanwal; Lodhi, Muhammad Arif; Wadood, Abdul; Riaz, Muhammad; Perveen, ShahnazBioorganic Chemistry (2019), 83 (), 29-46CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)Current study is based on the biol.-oriented drug synthesis (BIODS) of S-naproxen (NSAID) derivs. and the evaluation of their urease inhibitory potential. In this regard, a variety of S-naproxen derivs. 2-39 including hydrazide 1, Schiff bases 2-21, aroyl substituted hydrazides 22-24, sulfohydrazides 25-34, 2-mercapto oxadiazole 35, phenacyl substituted 2-mercapto oxadiazoles 36-39 were synthesized under the umbrella of BIODS by simple chem. transformation of its pharmacophoric carboxylic group. Compds. 1-39 were evaluated for in vitro urease inhibitory activity and most of them showed good to moderate inhibitory potential in the range of IC50 = 14.01±0.23-76.43±0.8 μM as compared to std. acetohydroxamic acid (IC50 = 27.0±0.5 μM). Limited structure-activity relationship (SAR) was established in order to rationalize the participation of varying groups (R) in the inhibitory potential of compds. Mol. docking study on all active compds. was also carried out to decipher the interactions detail of the ligand with the receptors of active site of enzyme.
- 54Mercorelli, B.; Palu, G.; Loregian, A. Drug repurposing for viral infectious diseases: how far are we?. Trends Microbiol. 2018, 26, 865– 876, DOI: 10.1016/j.tim.2018.04.004[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXos1Oitrc%253D&md5=6caf97ff2453b3dadcc0b54124a25d69Drug Repurposing for Viral Infectious Diseases: How Far Are WeMercorelli, Beatrice; Palu, Giorgio; Loregian, AriannaTrends in Microbiology (2018), 26 (10), 865-876CODEN: TRMIEA; ISSN:0966-842X. (Elsevier Ltd.)A review. Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral mols. and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery.
- 55Debing, Y.; Neyts, J.; Delang, L. The future of antivirals: broad-spectrum inhibitors. Curr. Opin. Infect. Dis. 2015, 28, 596– 602, DOI: 10.1097/QCO.0000000000000212[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVartLfF&md5=51aadcc17323e142ef8ba04f7b60b6c1The future of antivirals: broad-spectrum inhibitorsDebing, Yannick; Neyts, Johan; Delang, LeenCurrent Opinion in Infectious Diseases (2015), 28 (6), 596-602CODEN: COIDE5; ISSN:0951-7375. (Lippincott Williams & Wilkins)Purpose of review: Potent antivirals are successfully used for the treatment of infections with herpesviruses, hepatitis B and C viruses, HIV, and with some success for influenza viruses. However, no selective inhibitors are available for a multitude of medically important viruses, most of which are (re-)emerging RNA viruses. As it is impossible to develop drugs against each of these viruses, broad-spectrum antiviral agents (BSAA) are a prime strategy to cope with this challenge. Recent findings: We propose four categories of antiviral mols. that hold promise as BSAA. Several nucleoside analogs with broad antiviral activity have been described and given the relatively conserved nature of viral polymerases, it may be possible to develop more broad-spectrum nucleoside analogs. A no. of viral proteins are relatively conserved between families and may also be interesting targets. Host-targeting antiviral drugs such as modulators of lipid metab. and cyclophilin inhibitors can be explored as well. Finally, the potent and broad antiviral function of the immune system can be exploited by the development of immune-modulating BSAA. Summary: Despite the recent advances, the BSAA field is still in its infancy. Nevertheless, the discovery and development of such mols. will be a key aim of antiviral research in the coming decades.
- 56Sacramento, C. Q.; de Melo, G. R.; de Freitas, C. S.; Rocha, N.; Hoelz, L. V.; Miranda, M.; Fintelman-Rodrigues, N.; Marttorelli, A.; Ferreira, A. C.; Barbosa-Lima, G.; Abrantes, J. L.; Vieira, Y. R.; Bastos, M. M.; de Mello Volotao, E.; Nunes, E. P.; Tschoeke, D. A.; Leomil, L.; Loiola, E. C.; Trindade, P.; Rehen, S. K.; Bozza, F. A.; Bozza, P. T.; Boechat, N.; Thompson, F. L.; de Filippis, A. M.; Bruning, K.; Souza, T. M. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci. Rep. 2017, 7, 40920, DOI: 10.1038/srep40920[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVantL4%253D&md5=944e73ce2f50fa92d5d18e230a58ff2cThe clinically approved antiviral drug sofosbuvir inhibits Zika virus replicationSacramento, Carolina Q.; de Melo, Gabrielle R.; de Freitas, Caroline S.; Rocha, Natasha; Hoelz, Lucas Villas Boas; Miranda, Milene; Fintelman-Rodrigues, Natalia; Marttorelli, Andressa; Ferreira, Andre C.; Barbosa-Lima, Giselle; Abrantes, Juliana L.; Vieira, Yasmine Rangel; Bastos, Monica M.; de Mello Volotao, Eduardo; Nunes, Estevao Portela; Tschoeke, Diogo A.; Leomil, Luciana; Loiola, Erick Correia; Trindade, Pablo; Rehen, Stevens K.; Bozza, Fernando A.; Bozza, Patricia T.; Boechat, Nubia; Thompson, Fabiano L.; de Filippis, Ana M. B.; Bruning, Karin; Souza, Thiago Moreno L.Scientific Reports (2017), 7 (), 40920CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clin. significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurol. disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clin. approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addn. to the direct inhibition of the viral RNA polymerase, we obsd. that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.
- 57Abdelnabi, R.; Morais, A. T. S.; Leyssen, P.; Imbert, I.; Beaucourt, S.; Blanc, H.; Froeyen, M.; Vignuzzi, M.; Canard, B.; Neyts, J.; Delang, L. Understanding the mechanism of the broad-spectrum antiviral activity of favipiravir (T-705): key role of the F1 motif of the viral polymerase. J. Virol. 2017, 91, e00487, DOI: 10.1128/JVI.00487-17[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1elsrzE&md5=0bcc12b05ab01929161119020c735cf7Understanding the mechanism of the broad-spectrum antiviral activity of favipiravir (T-705): key role of the F1 motif of the viral polymeraseAbdelnabi, Rana; Silveira de Morais, Ana Theresa; Leyssen, Pieter; Imbert, Isabelle; Beaucourt, Stephanie; Blanc, Herve; Froeyen, Mathy; Vignuzzi, Marco; Canard, Bruno; Neyts, Johan; Delang, LeenJournal of Virology (2017), 91 (12), e00487-17/1-e00487-17/15CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of pos.-sense singlestranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis anal. at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme.
- 58Rossignol, J. F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014, 110, 94– 103, DOI: 10.1016/j.antiviral.2014.07.014[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisL%252FK&md5=12dd8a143876626fc31303da2c5f24c4Nitazoxanide: A first-in-class broad-spectrum antiviral agentRossignol, Jean-FrancoisAntiviral Research (2014), 110 (), 94-103CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. A Phase 2b/3 clin. trial recently published in The Lancet Infectious Diseases found that oral administration of nitazoxanide 600 mg twice daily for five days reduced the duration of clin. symptoms and reduced viral shedding compared to placebo in persons with lab.-confirmed influenza. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection. From a chem. perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-mol. drugs target host-regulated processes involved in viral replication. Nitazoxanide is orally bioavailable and safe with extensive post-marketing experience involving more than 75 million adults and children. A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clin. development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. It is synergistic with neuraminidase inhibitors, and combination therapy with oseltamivir is being studied in humans as part of ongoing Phase 3 clin. development. Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clin. trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clin. development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.
- 59(a) Li, C. C.; Wang, X. J.; Wang, H. R. Repurposing host-based therapeutics to control coronavirus and influenza virus. Drug Discov. Today 2019, 24, 726, DOI: 10.1016/j.drudis.2019.01.018[Crossref], [PubMed], [CAS], Google Scholar.59ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjot1KrsQ%253D%253D&md5=63715dbcbaa48ee2a7cd6e1adde992b9Repurposing host-based therapeutics to control coronavirus and influenza virusLi Cui-Cui; Wang Xiao-Jia; Wang Hwa-Chain RobertDrug discovery today (2019), 24 (3), 726-736 ISSN:.The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.(b) Meng, W.; Wang, X. J.; Wang, H. R. Targeting nuclear proteins for control of viral replication. Crit. Rev. Microbiol. 2019, 1– 19, DOI: 10.1080/1040841X.2018.1553848[Crossref], [PubMed], [CAS], Google Scholar59bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjjsVygug%253D%253D&md5=2220b446fbf713bc18f5ecae662a22f0Targeting nuclear proteins for control of viral replicationMeng Wen; Wang Xiao-Jia; Wang Hwa-Chain RobertCritical reviews in microbiology (2019), (), 1-19 ISSN:.Viruses are obligate intracellular parasites that exploit host cell machineries for replication. In this review, we focus on the current understanding of host cell nuclear proteins whose translocation from the nucleus to cytoplasm is induced and utilized by viruses to support viral replication and infection. Utilization of nuclear proteins for viral replication and infection involves disruption of nuclear import, enhancement of nuclear export, removal of nuclear localization signal (NLS) from nuclear proteins and alteration of nuclear pore complexes (NPCs) to cooperatively support viral replication. Understanding of nucleo-cytoplasmic transport system, and associated mechanisms, utilized by viruses will advance therapeutic development of strategies to produce optimal antiviral agents effective in control of viral diseases.
- 60Tong, X.; Smith, J.; Bukreyeva, N.; Koma, T.; Manning, J. T.; Kalkeri, R.; Kwong, A. D.; Paessler, S. Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. Antiviral Res. 2018, 149, 34– 40, DOI: 10.1016/j.antiviral.2017.11.004[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVSiu7bK&md5=959c9e0115298b3f1299d79a00a0c89aMerimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogensTong, Xiao; Smith, Jeanon; Bukreyeva, Natalya; Koma, Takaaki; Manning, John T.; Kalkeri, Raj; Kwong, Ann D.; Paessler, SlobodanAntiviral Research (2018), 149 (), 34-40CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to abnormal pregnancies, fetal death, microcephaly, and Guillain-Barre´ syndrome in humans. Merimepodib (MMPD, VX-497), a potent inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), has shown antiviral activity against HCV and a variety of DNA and RNA viruses in vitro. In this report, we expand the antiviral spectrum of MMPD, and demonstrate that MMPD inhibits ZIKV RNA replication with an EC50 of 0.6 μM. Furthermore, MMPD reduces the virus prodn. of ZIKV as well as several other important emerging viral pathogens such as Ebola, Lassa, Chikungunya, and Junin viruses. The inhibition can be reversed by addn. of exogenous guanosine to culture media, consistent with the mechanism of action of MMPD as an IMPDH inhibitor. We also provide evidence that MMPD can be used in combination with other antivirals such as ribavirin and T-705 (favipiravir) to enhance suppression of virus prodn.
- 61Dang, W.; Yin, Y.; Wang, Y.; Wang, W.; Su, J.; Sprengers, D.; van der Laan, L. J. W.; Felczak, K.; Pankiewicz, K. W.; Chang, K. O.; Koopmans, M. P. G.; Metselaar, H. J.; Peppelenbosch, M. P.; Pan, Q. Inhibition of calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replication. Antimicrob. Agents Chemother. 2017, 61, e01095– 17, DOI: 10.1128/AAC.01095-17[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsl2jtLc%253D&md5=248ed1305a71c7e46e6933a4fc5f46e7Inhibition of calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replicationDang, Wen; Yin, Yuebang; Wang, Yijin; Wang, Wenshi; Su, Junhong; Sprengers, Dave; van der Laan, Luc J. W.; Felczak, Krzysztof; Pankiewicz, Krzysztof W.; Chang, Kyeong-Ok; Koopmans, Marion P. G.; Metselaar, Herold J.; Peppelenbosch, Maikel P.; Pan, QiuweiAntimicrobial Agents and Chemotherapy (2017), 61 (11), e01095-17/1-e01095-17/17CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concn., therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.
- 62Hu, J.; Ma, L.; Wang, H.; Yan, H.; Zhang, D.; Li, Z.; Jiang, J.; Li, Y. A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5′-Monophospate dehydrogenase activity. Virol J. 2017, 14, 55, DOI: 10.1186/s12985-017-0724-6[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvVags7o%253D&md5=5478507bdcb798e9dd77da1bc0a84a26A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5'-Monophospate Dehydrogenase activityHu, Jin; Ma, Linlin; Wang, Huiqiang; Yan, Haiyan; Zhang, Dajun; Li, Zhuorong; Jiang, Jiandong; Li, YuhuanVirology Journal (2017), 14 (), 55/1-55/9CODEN: VJIOA4; ISSN:1743-422X. (BioMed Central Ltd.)Influenza virus is still a huge threat to the world-wide public health. Host inosine-5'- monophosphate dehydrogenase (IMPDH) involved in the synthesis of guanine nucleotides, is known to be a potential target to inhibit the replication of viruses. Herein, we evaluated antiviral activity of a benzo-heterocyclic amine deriv. N30, which was designed to inhibit IMPDH. The results demonstrated that N30 inhibited the replication of H1N1, H3N2, influenza B viruses, including oseltamivir and amantadine resistant strains in vitro. Mechanistically, neuraminidase inhibition assay and hemagglutination inhibition assay suggested that N30 did not directly target the two envelope glycoproteins required for viral adsorption or release. Instead, the compd. could depress the activity of IMPDH type II. Based on these findings, we further confirmed that N30 provided a strong inhibition on the replication of respiratory syncytial virus, coronavirus, enterovirus 71 and a diverse strains of coxsackie B virus. We identified the small mol. N30, as an inhibitor of IMPDH, might be a potential candidate to inhibit the replication of various viruses.
- 63Nair, V.; Chi, G.; Shu, Q.; Julander, J.; Smee, D. F. A heterocyclic molecule with significant activity against dengue virus. Bioorg. Med. Chem. Lett. 2009, 19, 1425– 1427, DOI: 10.1016/j.bmcl.2009.01.031[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXit1Wmsb8%253D&md5=87f61298ea3e49d74a87389aca4a36acA heterocyclic molecule with significant activity against dengue virusNair, Vasu; Chi, Guochen; Shu, Qingning; Julander, Justin; Smee, Donald F.Bioorganic & Medicinal Chemistry Letters (2009), 19 (5), 1425-1427CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The prepn. of two uracil-based multifunctional compds I [X = N (II), CH] was reported. One of these compds., II, showed strong activity against dengue virus. It also exhibited low activity against a few other RNA viruses, but was highly active against yellow fever virus, a related flavivirus. It is likely that the mechanism of action of the antiviral activity of this compd. is through its inhibition of the enzyme, inosine monophosphate dehydrogenase (IMPDH). Mol. modeling studies revealed that the compd. can have specific hydrogen bonding interactions with a no. of amino acids in the active site of IMPDH, a stacking interaction with the bound natural substrate, IMP, and the ability to interfere with the binding of NAD+ with IMPDH, prior to the hydration step.
- 64Mejdrova, I.; Chalupska, D.; Plackova, P.; Muller, C.; Sala, M.; Klima, M.; Baumlova, A.; Hrebabecky, H.; Prochazkova, E.; Dejmek, M.; Strunin, D.; Weber, J.; Lee, G.; Matousova, M.; Mertlikova-Kaiserova, H.; Ziebuhr, J.; Birkus, G.; Boura, E.; Nencka, R. Rational design of novel highly potent and selective phosphatidylinositol 4-kinase IIIbeta (PI4KB) inhibitors as broad-spectrum antiviral agents and tools for chemical biology. J. Med. Chem. 2017, 60, 100– 118, DOI: 10.1021/acs.jmedchem.6b01465[ACS Full Text], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGitbbM&md5=d0cc3a744b59313677b10454012c495bRational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical BiologyMejdrova, Ivana; Chalupska, Dominika; Plackova, Pavla; Muller, Christin; Sala, Michal; Klima, Martin; Baumlova, Adriana; Hrebabecky, Hubert; Prochazkova, Eliska; Dejmek, Milan; Strunin, Dmytro; Weber, Jan; Lee, Gary; Matousova, Marika; Mertlikova-Kaiserova, Helena; Ziebuhr, John; Birkus, Gabriel; Boura, Evzen; Nencka, RadimJournal of Medicinal Chemistry (2017), 60 (1), 100-118CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various pos.-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, the authors report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compds. exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. The authors' crystallog. anal. unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.
- 65Bauer, L.; Ferla, S.; Head, S. A.; Bhat, S.; Pasunooti, K. K.; Shi, W. Q.; Albulescu, L.; Liu, J. O.; Brancale, A.; van Kuppeveld, F. J. M.; Strating, J. R. P. M. Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP). Antiviral Res. 2018, 156, 55– 63, DOI: 10.1016/j.antiviral.2018.05.010[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWitbjO&md5=457ee3152a08fd4640aa6e87be8467c5Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP)Bauer, Lisa; Ferla, Salvatore; Head, Sarah A.; Bhat, Shridhar; Pasunooti, Kalyan K.; Shi, Wei Q.; Albulescu, Lucian; Liu, Jun O.; Brancale, Andrea; van Kuppeveld, Frank J. M.; Strating, Jeroen R. P. M.Antiviral Research (2018), 156 (), 55-63CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Itraconazole (ITZ) is a well-known, FDA-approved antifungal drug that is also in clin. trials for its anticancer activity. ITZ exerts its anticancer activity through several disparate targets and pathways. ITZ inhibits angiogenesis by hampering the functioning of the vascular endothelial growth receptor 2 (VEGFR2) and by indirectly inhibiting mTOR signaling. Furthermore, ITZ directly inhibits the growth of several types of tumor cells by antagonizing Hedgehog signaling. Recently, we reported that ITZ also has broad-spectrum antiviral activity against enteroviruses, cardioviruses and hepatitis C virus, independent of established ITZ-activities but instead via a novel target, oxysterol-binding protein (OSBP), a cellular lipid shuttling protein. In this study, we analyzed which structural features of ITZ are important for the OSBP-mediated antiviral activity. The backbone structure, consisting of five rings, and the sec-Bu chain are important for antiviral activity, whereas the triazole moiety, which is crit. for antifungal activity, is not. The features required for OSBP-mediated antiviral activity of ITZ overlap mostly with published features required for inhibition of VEGFR2 trafficking, but not Hh signaling. Furthermore, we use in silico studies to explore how ITZ could bind to OSBP. Our data show that several pharmacol. activities of ITZ can be uncoupled, which is a crit. step in the development of ITZ-based antiviral compds. with greater specificity and reduced off-target effects.
- 66(a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. Rings in drugs. J. Med. Chem. 2014, 57, 5845– 5859, DOI: 10.1021/jm4017625[ACS Full Text.], [CAS], Google Scholar66ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCntbc%253D&md5=c84ce84b8698eb6fad38fa82b0ab4912Rings in DrugsTaylor, Richard D.; MacCoss, Malcolm; Lawson, Alastair D. G.Journal of Medicinal Chemistry (2014), 57 (14), 5845-5859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, time-lines, mol. property space, and the application of these rings in different therapeutic areas and target classes. This anal. shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on av. six new ring systems enter drug space each year and approx. 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chem. novelty of drugs and potentially efficient ways to assess compd. libraries and develop compds. from hit identification to lead optimization and beyond.(b) Taylor, R. D.; MacCoss, M.; Lawson, A. D. Combining molecular scaffolds from FDA approved drugs: application to drug discovery. J. Med. Chem. 2017, 60, 1638– 1647, DOI: 10.1021/acs.jmedchem.6b01367[ACS Full Text], [CAS], Google Scholar66bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGrurrJ&md5=b4fea6326e337e85d39aa827a180b634Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug DiscoveryTaylor, Richard D.; MacCoss, Malcolm; Lawson, Alastair D. G.Journal of Medicinal Chemistry (2017), 60 (5), 1638-1647CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The authors have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in-silico database of approx. 14 million mols. This virtual library was compared with mol. databases of published and com. available compds. to assess the prevalence of drug ring combinations in modern medicinal chem. and to identify areas of under-represented, but clin. validated, chem. space. From the 10 trillion mol. comparisons, the authors found that less than 1% of the possible combinations of drug ring systems appear in com. available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small mol. drug discovery, as based on the previous anal. (Taylor et al. J. Med. Chem. 2014; 57: 5845-9) approx. 70% of all new drugs are made up of only ring systems that have been used in existing drugs.
- 67(a) Song, Y.; Chen, W.; Kang, D.; Zhang, Q.; Zhan, P.; Liu, X. ″Old friends in new guise″: exploiting privileged structures for scaffold re-evolution/refining. Comb. Chem. High Throughput Screening 2014, 17, 536– 553, DOI: 10.2174/1386207317666140122101631[Crossref], [PubMed], [CAS], Google Scholar.67ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOgsLvF&md5=4353d66dbd43353caefcd150938f94cd"Old Friends in New Guise": Exploiting Privileged Structures for Scaffold Re-Evolution/RefiningSong, Yu'ning; Chen, Wenmin; Kang, Dongwei; Zhang, Qingzhu; Zhan, Peng; Liu, XinyongCombinatorial Chemistry & High Throughput Screening (2014), 17 (6), 536-553CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)A review. The attempts to increase novel drug productivity through creative discovery technologies have fallen short of producing the satisfactory results. For these reasons, evolved from the concept of drug repositioning, "privileged structure"-guided scaffold re-evolution/refining is a primary strategy to identify structurally novel chemotypes by modifying the central core structure and the side-chain of the existing active compds., or to exploit undescribed bioactivites by making full use of readily derivatized motifs with well-established synthetic protocols. Herein, we review the basic tricks of exploiting privileged structures for scaffold re-evolution/refining. The power of this strategy is exemplified in the discovery of other new therapeutic applications by refining privileged structures in anti-viral agents.(b) Li, Z.; Zhan, P.; Liu, X. 1,3,4-oxadiazole: a privileged structure in antiviral agents. Mini-Rev. Med. Chem. 2011, 11, 1130– 1142, DOI: 10.2174/138955711797655407[Crossref], [PubMed], [CAS], Google Scholar.67bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFakt7jJ&md5=440a9792afb05d86aafaf53379861dcb1,3,4-oxadiazole: a privileged structure in antiviral agentsLi, Z.; Zhan, P.; Liu, X.Mini-Reviews in Medicinal Chemistry (2011), 11 (13), 1130-1142CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. 1,3,4-Oxadiazole, a privileged structure, endows its derivs. with broad and potent biol. functions, esp. in antiviral activities, including anti-HIV, anti-HCV, anti-HBV, anti-HSV activities, etc. Mol. modeling and pharmacokinetic studies have demonstrated that the introduction of 1,3,4-oxadiazole ring to the inhibitors can change their polarity, flexibility as well as metabolic stability, and 1,3,4-oxadiazole scaffold can also act as acceptors of hydrogen bonds formation, which make it possible to be used as a isosteric substituent for amide or ester groups. This review focuses on the recent advances in the synthesis of 1,3,4-oxadiazole ring and mainly the discovery, biol. activities investigations and structural modifications of several distinct classes of 1,3,4-oxadiazoles as potent antiviral agents. In addn., the binding models of some representative 1,3,4-oxadiazoles were also discussed, which provide rational explanation for their interesting antiviral activities, and also pave the way for further optimization of 1,3,4- oxadiazole based antiviral agents.(c) Song, Y.; Zhan, P.; Zhang, Q.; Liu, X. Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry. Curr. Pharm. Des. 2013, 19, 1528– 1548, DOI: 10.2174/138161213804805559[Crossref], [PubMed], [CAS], Google Scholar.67chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlt1Gnsrs%253D&md5=b6ca8b08c0daadbf0b35f800266115a3Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistrySong, Yu'ning; Zhan, Peng; Zhang, Qingzhu; Liu, XinyongCurrent Pharmaceutical Design (2013), 19 (8), 1528-1548CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivs. with a wide range of biol. activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogen-activated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biol. properties of pyrrolo[2,1-f][1,2,4]triazine derivs. have motivated new studies in searching for novel derivs. with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1-f][1,2,4]triazine derivs. concerning the design of potent drug-like compds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacol. activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.(d) Song, Y.; Zhan, P.; Liu, X. Heterocycle-thioacetic acid motif: a privileged molecular scaffold with potent, broad-ranging pharmacological activities. Curr. Pharm. Des. 2013, 19, 7141– 7154, DOI: 10.2174/13816128113199990505[Crossref], [PubMed], [CAS], Google Scholar.67dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFelur7K&md5=c2e4d68cc73d6108468a2f310f428b09Heterocycle-thioacetic Acid Motif: A Privileged Molecular Scaffold with Potent, Broad-Ranging Pharmacological ActivitiesSong, Yu'ning; Zhan, Peng; Liu, XinyongCurrent Pharmaceutical Design (2013), 19 (40), 7141-7154CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Privileged structures can bind to multiple targets with high affinity, thus aiding the discovery of novel bioactive agents. Heterocycle-thioacetic acid derivs., a group of mols. contg. a heterocycle core linked with a thioacetic acid-derived fragment, represent an important type of "privileged scaffold" possessing a wide spectrum of biol. properties. Numerous encouraging investigations demonstrated that this privileged structure should be extensively exploited for the therapeutic benefits. In view of its predominance, and on the basis of our research interest involved in this scaffold, an updated and detailed account of the pharmacol. properties of heterocycle-thioacetic acid derivs. is described in this article.(e) Zhao, F.; Liu, N.; Zhan, P.; Liu, X. Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricks. Future Med. Chem. 2015, 7, 1367– 1371, DOI: 10.4155/fmc.15.76[Crossref], [PubMed], [CAS], Google Scholar67ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmtrvO&md5=817927f51219a6e23073d4b26e6c1ac0Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricksZhao, Fabao; Liu, Na; Zhan, Peng; Liu, XinyongFuture Medicinal Chemistry (2015), 7 (11), 1367-1371CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)There is no expanded citation for this reference.
- 68Zeng, L. F.; Wang, Y.; Kazemi, R.; Xu, S.; Xu, Z. L.; Sanchez, T. W.; Yang, L. M.; Debnath, B.; Odde, S.; Xie, H.; Zheng, Y. T.; Ding, J.; Neamati, N.; Long, Y. Q. Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties. J. Med. Chem. 2012, 55, 9492– 9509, DOI: 10.1021/jm300667v[ACS Full Text], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOltrvN&md5=1dfedb7d079e37cdd5244253e351e2dfRepositioning HIV-1 Integrase Inhibitors for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold with Drug-like PropertiesZeng, Li-Fan; Wang, Yong; Kazemi, Roza; Xu, Shili; Xu, Zhong-Liang; Sanchez, Tino W.; Yang, Liu-Meng; Debnath, Bikash; Odde, Srinivas; Xie, Hua; Zheng, Yong-Tang; Ding, Jian; Neamati, Nouri; Long, Ya-QiuJournal of Medicinal Chemistry (2012), 55 (22), 9492-9509CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Among a large no. of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Labs. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clin. studies, development of L-870,810 was halted. Because of its desirable pharmacol. and pharmaceutical properties we were intrigued to design novel analogs of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines, e.g. I [R = OH, NHCH2CH2OH, NHBn, etc.], were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compds. with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.
- 69Schwehm, C.; Kellam, B.; Garces, A. E.; Hill, S. J.; Kindon, N. D.; Bradshaw, T. D.; Li, J.; Macdonald, S. J.; Rowedder, J. E.; Stoddart, L. A.; Stocks, M. J. Design and Elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C-C chemokine receptor type 5 (CCR5), and highly potent and selective phosphoinositol-3 kinase delta (PI3Kdelta) inhibitors. J. Med. Chem. 2017, 60, 1534– 1554, DOI: 10.1021/acs.jmedchem.6b01801[ACS Full Text], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gjtbg%253D&md5=9128aca7e5568a89cb49addccdc3283aDesign and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) InhibitorsSchwehm, Carolin; Kellam, Barrie; Garces, Aimie E.; Hill, Stephen J.; Kindon, Nicholas D.; Bradshaw, Tracey D.; Li, Jin; Macdonald, Simon J. F.; Rowedder, James E.; Stoddart, Leigh A.; Stocks, Michael J.Journal of Medicinal Chemistry (2017), 60 (4), 1534-1554CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel mol. scaffold has been synthesized, and its incorporation into new analogs of biol. active mols. across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochem. properties of the resulting inhibitors and conclude that the tractable mol. scaffold could have potential application in future drug discovery programs.
- 70John, J.; Kim, Y.; Bennett, N.; Das, K.; Liekens, S.; Naesens, L.; Arnold, E.; Maguire, A. R.; Gotte, M.; Dehaen, W.; Balzarini, J. Pronounced inhibition shift from HIV reverse transcriptase to herpetic DNA polymerases by increasing the flexibility of alpha-carboxy nucleoside phosphonates. J. Med. Chem. 2015, 58, 8110– 8127, DOI: 10.1021/acs.jmedchem.5b01180[ACS Full Text], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Kit7fO&md5=870e3e13a71997e19138133dbb3eacf2Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside PhosphonatesJohn, Jubi; Kim, Youngju; Bennett, Nicholas; Das, Kalyan; Liekens, Sandra; Naesens, Lieve; Arnold, Eddy; Maguire, Anita R.; Gotte, Matthias; Dehaen, Wim; Balzarini, JanJournal of Medicinal Chemistry (2015), 58 (20), 8110-8127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)α-Carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodol. involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.
- 71(a) Nowotny, M. Retroviral integrase superfamily: the structural perspective. EMBO Rep. 2009, 10, 144– 151, DOI: 10.1038/embor.2008.256[Crossref], [PubMed], [CAS], Google Scholar.71ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsVChsg%253D%253D&md5=8e67d5e63bdc6e84a3f7576cd6eaa74cRetroviral integrase superfamily: the structural perspectiveNowotny, MarcinEMBO Reports (2009), 10 (2), 144-151CODEN: ERMEAX; ISSN:1469-221X. (Nature Publishing Group)A review. The retroviral integrase superfamily (RISF) comprises numerous important nucleic acid-processing enzymes, including transposases, integrases and various nucleases. These enzymes are involved in a wide range of processes such as transposition, replication and repair of DNA, homologous recombination, and RNA-mediated gene silencing. Two out of the four enzymes that are encoded by the human immunodeficiency virus, RNase H1 and integrase, are members of this superfamily. RISF enzymes act on various substrates, and yet show remarkable mechanistic and structural similarities. All share a common fold of the catalytic core and the active site, which is composed primarily of carboxylate residues. Here, RISF proteins are presented from a structural perspective, describing the individual members and the common and divergent elements of their structures, as well as the mechanistic insights gained from the structures of RNase H1 enzyme complexes with RNA/DNA hybrids.(b) Majorek, K. A.; Dunin-Horkawicz, S.; Steczkiewicz, K.; Muszewska, A.; Nowotny, M.; Ginalski, K.; Bujnicki, J. M. The RNase H-like superfamily: new members, comparative structural analysis and evolutionary classification. Nucleic Acids Res. 2014, 42, 4160– 4179, DOI: 10.1093/nar/gkt1414[Crossref], [PubMed], [CAS], Google Scholar71bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtFSitLw%253D&md5=48cff800010a8087efcfcd1eca203ebcThe RNase H-like superfamily: new members, comparative structural analysis and evolutionary classificationMajorek, Karolina A.; Dunin-Horkawicz, Stanislaw; Steczkiewicz, Kamil; Muszewska, Anna; Nowotny, Marcin; Ginalski, Krzysztof; Bujnicki, Janusz M.Nucleic Acids Research (2014), 42 (7), 4160-4179CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)RNase H-like (RNHL) superfamily, also called the retroviral integrase superfamily, groups together numerous enzymes involved in nucleic acid metab. and implicated in many biol. processes, including replication, homologous recombination, DNA repair, transposition and RNA interference. The RNHL superfamily proteins show extensive divergence of sequences and structures. The authors conducted database searches to identify members of the RNHL superfamily (including those previously unknown), yielding >60 000 unique domain sequences. Their anal. led to the identification of new RNHL superfamily members, such as RRXRR (PF14239), DUF460 (PF04312, COG2433), DUF3010 (PF11215), DUF429 (PF04250 and COG2410, COG4328, COG4923), DUF1092 (PF06485), COG5558, OrfB_IS605 (PF01385, COG0675) and Peptidase_A17 (PF05380). Based on the clustering anal., the authors grouped all identified RNHL domain sequences into 152 families. Phylogenetic studies revealed relationships between these families, and suggested a possible history of the evolution of RNHL fold and its active site. The results revealed clear division of the RNHL superfamily into exonucleases and endonucleases. Structural analyses of features characteristic for particular groups revealed a correlation between the orientation of the C-terminal helix with the exonuclease/endonuclease function and the architecture of the active site. This anal. provides a comprehensive picture of sequence-structure-function relationships in the RNHL superfamily that may guide functional studies of the previously uncharacterized protein families.
- 72(a) Xu, P.; Ganaie, S. S.; Wang, X.; Wang, Z.; Kleiboeker, S.; Horton, N. C.; Heier, R. F.; Meyers, M. J.; Tavis, J. E.; Qiu, J. Endonuclease activity inhibition of the NS1 protein of parvovirus B19 as a novel target for antiviral drug development. Antimicrob. Agents Chemother. 2019, 63, AAC.01879, DOI: 10.1128/AAC.01879-18 .(b) Tavis, J. E.; Zoidis, G.; Meyers, M. J.; Murelli, R. P. Chemical approaches to inhibiting the hepatitis B virus ribonuclease H. ACS Infect. Dis. 2018, DOI: 10.1021/acsinfecdis.8b00045 .(c) Lomonosova, E.; Daw, J.; Garimallaprabhakaran, A. K.; Agyemang, N. B.; Ashani, Y.; Murelli, R. P.; Tavis, J. E. Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H. Antiviral Res. 2017, 144, 164– 172, DOI: 10.1016/j.antiviral.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar.72chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKntrjN&md5=b8f6cf6d2ba37d8d8d7bba073505e92eEfficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease HLomonosova, Elena; Daw, Jil; Garimallaprabhakaran, Aswin K.; Agyemang, Nana B.; Ashani, Yashkumar; Murelli, Ryan P.; Tavis, John E.Antiviral Research (2017), 144 (), 164-172CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral RNase H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α-hydroxytropolone compds. can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochem. RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity anal. of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.(d) Edwards, T. C.; Lomonosova, E.; Patel, J. A.; Li, Q.; Villa, J. A.; Gupta, A. K.; Morrison, L. A.; Bailly, F.; Cotelle, P.; Giannakopoulou, E.; Zoidis, G.; Tavis, J. E. Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles. Antiviral Res. 2017, 143, 205– 217, DOI: 10.1016/j.antiviral.2017.04.012[Crossref], [PubMed], [CAS], Google Scholar.72dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVaqtrk%253D&md5=3e1ded73ed62966b49f39182d38d00c4Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocyclesEdwards, Tiffany C.; Lomonosova, Elena; Patel, Jenny A.; Li, Qilan; Villa, Juan A.; Gupta, Ankit K.; Morrison, Lynda A.; Bailly, Fabrice; Cotelle, Philippe; Giannakopoulou, Erofili; Zoidis, Grigoris; Tavis, John E.Antiviral Research (2017), 143 (), 205-217CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)We previously reported low sensitivity of the hepatitis B virus (HBV) RNase H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compds. Subsequently, our biochem. RNaseH assay was found to have a high false neg. rate for predicting HBV replication inhibition, leading to underestimation of the no. of HIDs that inhibit HBV replication. Here, 39 HID compds. and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the pos.-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV pos.-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indexes from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.(e) Lu, G.; Lomonosova, E.; Cheng, X.; Moran, E. A.; Meyers, M. J.; Le Grice, S. F.; Thomas, C. J.; Jiang, J. K.; Meck, C.; Hirsch, D. R.; D’Erasmo, M. P.; Suyabatmaz, D. M.; Murelli, R. P.; Tavis, J. E. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob. Agents Chemother. 2015, 59, 1070– 1079, DOI: 10.1128/AAC.04617-14[Crossref], [PubMed], [CAS], Google Scholar.72ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1Kqsrg%253D&md5=ad57f43a17b6aaf4a68a5912a7e72c1eHydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activityLu, Gaofeng; Lomonosova, Elena; Cheng, Xiaohong; Moran, Eileen A.; Meyers, Marvin J.; Le Grice, Stuart F. J.; Thomas, Craig J.; Jiang, Jian-kang; Meck, Christine; Hirsch, Danielle R.; D'Erasmo, Michael P.; Suyabatmaz, Duygu M.; Murelli, Ryan P.; Tavis, John E.Antimicrobial Agents and Chemotherapy (2015), 59 (2), 1070-1079, 10 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compds. for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of detg. whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compds. inhibited HBV RNaseH, with the best 50% inhibitory concn. (IC50) being 2.3 μM. Similar inhibition patterns were obsd. against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compds. tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concn. (EC50) being 0.34 μM. Eighteen compds. inhibited recombinant human RNaseH1, and moderate cytotoxicity was obsd. for all compds. (50% cytotoxic concn. [CC50] = 25 to 79 μM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.(f) Cai, C. W.; Lomonosova, E.; Moran, E. A.; Cheng, X.; Patel, K. B.; Bailly, F.; Cotelle, P.; Meyers, M. J.; Tavis, J. E. Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Res. 2014, 108, 48– 55, DOI: 10.1016/j.antiviral.2014.05.007[Crossref], [PubMed], [CAS], Google Scholar.72fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGqsrnE&md5=790a7c0b6496897f62a68cbcfc747135Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activityCai, Catherine W.; Lomonosova, Elena; Moran, Eileen A.; Cheng, Xiaohong; Patel, Kunjan B.; Bailly, Fabrice; Cotelle, Philippe; Meyers, Marvin J.; Tavis, John E.Antiviral Research (2014), 108 (), 48-55CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Nucleos(t)ide analog drugs profoundly suppress Hepatitis B virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV RNase H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivs. for anti-HBV RNaseH activity. Nine compds. inhibited the HBV RNaseH, but activity was marginal for eight of them. Compd. #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1 μM and an EC50 of 4.2 μM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75 μM, yielding a therapeutic index of ∼18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metab. of the compd., or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure-activity relationships for the HBV and HIV RNaseHs. Therefore, HID compds. may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.(g) Hu, Y.; Cheng, X.; Cao, F.; Huang, A.; Tavis, J. E. β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity. Antiviral Res. 2013, 99, 221– 229, DOI: 10.1016/j.antiviral.2013.06.007[Crossref], [PubMed], [CAS], Google Scholar.72ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFentrfI&md5=eef4048551eda1f278210bc4d68f9563β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activityHu, Yuan; Cheng, Xiaohong; Cao, Feng; Huang, Ailong; Tavis, John E.Antiviral Research (2013), 99 (3), 221-229CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >350 million people and kills about 1 million patients annually. Therapy primarily employs nucleos(t)ide analogs that suppress viral DNA synthesis by the viral reverse transcriptase very well but that rarely cure the infection, so addnl. therapies are needed. Reverse transcription requires the viral RNase H (RNAseH) to destroy the viral RNA after it has been copied into DNA. We recently produced active recombinant HBV RNAseH and demonstrated that Human Immunodeficiency Virus (HIV) RNAseH antagonists could inhibit the HBV enzyme at a high frequency. Here, we extended these results to β-thujaplicinol, a hydroxylated tropolone which inhibits the HIV RNAseH. β-Thujaplicinol inhibited RNAseHs from HBV genotype D and H in biochem. assays with IC50 values of 5.9 ± 0.7 and 2.3 ± 1.7 μM, resp. It blocked replication of HBV genotypes A and D in culture by inhibiting the RNAseH activity with an estd. EC50 of ∼5 μM and a CC50 of 10.1 ± 1.7 μM. Activity of β-thujaplicinol against RNAseH sequences from multiple HBV genotypes implies that if chem. derivs. of β-thujaplicinol with improved efficacy and reduced toxicity can be identified, they would have promise as anti-HBV agents.(h) Tavis, J. E.; Cheng, X.; Hu, Y.; Totten, M.; Cao, F.; Michailidis, E.; Aurora, R.; Meyers, M. J.; Jacobsen, E. J.; Parniak, M. A.; Sarafianos, S. G. The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Pathog. 2013, 9, e1003125, DOI: 10.1371/journal.ppat.1003125[Crossref], [PubMed], [CAS], Google Scholar.72hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXivVOrsbg%253D&md5=f7841946904e4fe9ae6cc7a7b4502de5The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymesTavis, John E.; Cheng, Xiaohong; Hu, Yuan; Totten, Michael; Cao, Feng; Michailidis, Eleftherios; Aurora, Rajeev; Meyers, Marvin J.; Jacobsen, E. Jon; Parniak, Michael A.; Sarafianos, Stefan G.PLoS Pathogens (2013), 9 (1), e1003125CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV RNase H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatog. HBV RNAseH activity in the enriched lysates was characterized in prepn. for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chem. structureactivity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compds. inhibited the HBV RNAseH at 10 μM, the best compds. had low micromolar IC50 values against the RNAseH and one compd. inhibited HBV replication in tissue culture at 10 μM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compds. developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development.(i) Ireland, P. J.; Tavis, J. E.; D’Erasmo, M. P.; Hirsch, D. R.; Murelli, R. P.; Cadiz, M. M.; Patel, B. S.; Gupta, A. K.; Edwards, T. C.; Korom, M.; Moran, E. A.; Morrison, L. A. Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents Chemother. 2016, 60, 2140– 2149, DOI: 10.1128/AAC.02675-15[Crossref], [PubMed], [CAS], Google Scholar72ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1WqtLrJ&md5=f836b99afbd3c106a54b3fbc2dc62d38Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex virusesIreland, Peter J.; Tavis, John E.; D'Erasmo, Michael P.; Hirsch, Danielle R.; Murelli, Ryan P.; Cadiz, Mark M.; Patel, Bindi S.; Gupta, Ankit K.; Edwards, Tiffany C.; Korom, Maria; Moran, Eileen A.; Morrison, Lynda A.Antimicrobial Agents and Chemotherapy (2016), 60 (4), 2140-2149CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently detd. that certain natural troponoid compds. such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of detg. a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compds. inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compds. inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being obsd. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concn. (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was obsd. for all compds. (50% cytotoxic concn. [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.
- 73(a) Huber, A. D.; Michailidis, E.; Tang, J.; Puray-Chavez, M. N.; Boftsi, M.; Wolf, J. J.; Boschert, K. N.; Sheridan, M. A.; Leslie, M. D.; Kirby, K. A.; Singh, K.; Mitsuya, H.; Parniak, M. A.; Wang, Z.; Sarafianos, S. G. 3-Hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease H. Antimicrob. Agents Chemother. 2017, 61, e00245, DOI: 10.1128/AAC.00245-17[Crossref], [PubMed], [CAS], Google Scholar.73ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1SksrnL&md5=d519420e094913750925848d522fcdb93-Hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease HHuber, Andrew D.; Michailidis, Eleftherios; Tang, Jing; Puray-Chavez, Maritza N.; Boftsi, Maria; Wolf, Jennifer J.; Boschert, Kelsey N.; Sheridan, Megan A.; Leslie, Maxwell D.; Kirby, Karen A.; Singh, Kamalendra; Mitsuya, Hiroaki; Parniak, Michael A.; Wang, Zhengqiang; Sarafianos, Stefan G.Antimicrobial Agents and Chemotherapy (2017), 61 (6), e00245/1-e00245/5CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compds. inhibited HBV replication in the low micromolar range.(b) Wu, B.; Tang, J.; Wilson, D. J.; Huber, A. D.; Casey, M. C.; Ji, J.; Kankanala, J.; Xie, J.; Sarafianos, S. G.; Wang, Z. 3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides potently inhibit HIV-1 integrase and RNase H. J. Med. Chem. 2016, 59, 6136– 6148, DOI: 10.1021/acs.jmedchem.6b00040[ACS Full Text.], [CAS], Google Scholar73bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsFejs78%253D&md5=6914ec727a0308a1de9ec38f9db6134d3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase HWu, Bulan; Tang, Jing; Wilson, Daniel J.; Huber, Andrew D.; Casey, Mary C.; Ji, Juan; Kankanala, Jayakanth; Xie, Jiashu; Sarafianos, Stefan G.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (13), 6136-6148CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochem. testing and mol. modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogs also potently inhibited reverse transcriptase (RT) assocd. RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochem. properties suitable for further development.(c) Kankanala, J.; Kirby, K. A.; Liu, F.; Miller, L.; Nagy, E.; Wilson, D. J.; Parniak, M. A.; Sarafianos, S. G.; Wang, Z. Design, synthesis, and biological evaluations of hydroxypyridonecarboxylic acids as inhibitors of hiv reverse transcriptase associated RNase H. J. Med. Chem. 2016, 59, 5051– 5062, DOI: 10.1021/acs.jmedchem.6b00465[ACS Full Text.], [CAS], Google Scholar73chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsVams78%253D&md5=856a8a2c2d0c3c150ef845fb63db4e97Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase HKankanala, Jayakanth; Kirby, Karen A.; Liu, Feng; Miller, Lena; Nagy, Eva; Wilson, Daniel J.; Parniak, Michael A.; Sarafianos, Stefan G.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (10), 5051-5062CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeting the clin. unvalidated reverse transcriptase (RT) assocd. RNase H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biol. evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochem. studies show that most analogs consistently inhibited HIV RT-assocd. RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. Compd. I showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallog. studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogs.(d) Tang, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Wu, B.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. 3-Hydroxypyrimidine-2,4-diones as selective active site inhibitors of hiv reverse transcriptase-associated RNase H: design, synthesis, and biochemical evaluations. J. Med. Chem. 2016, 59, 2648– 2659, DOI: 10.1021/acs.jmedchem.5b01879[ACS Full Text.], [CAS], Google Scholar73dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsFaqtrg%253D&md5=906db68a78f7877f8bd8404227903dd83-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical EvaluationsTang, Jing; Liu, Feng; Nagy, Eva; Miller, Lena; Kirby, Karen A.; Wilson, Daniel J.; Wu, Bulan; Sarafianos, Stefan G.; Parniak, Michael A.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (6), 2648-2659CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human immunodeficiency virus (HIV) reverse transcriptase (RT) assocd. RNase H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochem. evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochem. studies showed the two subtypes with an N-1 Me group inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype, e.g., I, inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.(e) Wang, Y.; Tang, J.; Wang, Z.; Geraghty, R. J. Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication. Antiviral Res. 2018, 152, 10– 17, DOI: 10.1016/j.antiviral.2018.01.015[Crossref], [PubMed], [CAS], Google Scholar73ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1ansbw%253D&md5=fdd73309010aa57d6a7a835a10440b34Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replicationWang, Yan; Tang, Jing; Wang, Zhengqiang; Geraghty, Robert J.Antiviral Research (2018), 152 (), 10-17CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus prodn. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compds. featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC50 values in the enzymic assay and low micromolar EC50 values for inhibition of HCMV replication. Two representative compds. inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells.
- 74(a) Sun, L.; Gao, P.; Dong, G.; Zhang, X.; Cheng, X.; Ding, X.; Wang, X.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Menéndez-Arias, L.; Zhan, P.; Liu, X. 5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase. Eur. J. Med. Chem. 2018, 155, 714– 724, DOI: 10.1016/j.ejmech.2018.06.036[Crossref], [PubMed], [CAS], Google Scholar.74ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtF2qtbbF&md5=7b819ac0d1ba0d1a2dae8a1e3a7242755-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integraseSun, Lin; Gao, Ping; Dong, Guanyu; Zhang, Xujie; Cheng, Xiqiang; Ding, Xiao; Wang, Xueshun; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Menendez-Arias, Luis; Zhan, Peng; Liu, XinyongEuropean Journal of Medicinal Chemistry (2018), 155 (), 714-724CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Herein the design, synthesis and biol. evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivs. I (R = 1-naphthyl, 1,1'-biphenyl, 4-(pyrimidin-5-yl)phenyl, etc.) as HIV-1 reverse transcriptase (RT) RNase H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy was reported. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, IN inhibition assays was also performed. Notably, the majority of these derivs. inhibited RNase H and IN at micromolar concns. Among them, compd. I (R = 4'-cyano-[1,1'-biphenyl]) exhibited similar inhibitory activity against RNase H and IN (IC50RNase H = 1.77 μM, IC50IN = 1.18 μM, ratio = 1.50). To the best of knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Mol. modeling has been used to predict the binding mode of I (R = 4'-cyano-[1,1'-biphenyl]) in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compds. appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 mols. with suitable drug profiles.(b) Gao, P.; Zhang, L.; Sun, L.; Huang, T.; Tan, J.; Zhang, J.; Zhou, Z.; Zhao, T.; Menéndez-Arias, L.; Pannecouque, C.; Clercq, E.; Zhan, P.; Liu, X. 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries. Bioorg. Med. Chem. 2017, 25, 5779– 5789, DOI: 10.1016/j.bmc.2017.09.006[Crossref], [PubMed], [CAS], Google Scholar.74bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGns7vJ&md5=1f5a9b575ef2004c9651850a0da2eaa31-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound librariesGao, Ping; Zhang, Lingzi; Sun, Lin; Huang, Tianguang; Tan, Jing; Zhang, Jian; Zhou, Zhongxia; Zhao, Tong; Menendez-Arias, Luis; Pannecouque, Christophe; Clercq, Erik De; Zhan, Peng; Liu, XinyongBioorganic & Medicinal Chemistry (2017), 25 (20), 5779-5789CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A small library contg. 3-hydroxyquinazoline-2,4(1H,3H)-diones I (R = C6H5CH2, 4-FC6H4CH2, 2-CH3C6H4CH2, etc.) and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones II (R1 = C6H5(CH2)2, naphthalene-1-yl, C6H5NHC(O)CH2, etc.), III (R2 = 4-FC6H4CH2, 4-CH3C6H4CH2) was obtained via the copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compds., several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivs. II and III showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85 μM. The most active one, II (R = 4-FC6H4CH2) also showed remarkable and selective potency against HIV type 1 integrase (IN). This is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones II and III are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Mol. modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.(c) Wang, X.; Gao, P.; Menendez-Arias, L.; Liu, X.; Zhan, P. Update on recent developments in small molecular hiv-1 rnase h inhibitors (2013–2016): opportunities and challenges. Curr. Med. Chem. 2018, 25, 1682– 1702, DOI: 10.2174/0929867324666170113110839[Crossref], [PubMed], [CAS], Google Scholar.74chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVWksr7L&md5=174f7026aa10084247e9d4968c7b8923Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013-2016): Opportunities and ChallengesWang, Xueshun; Gao, Ping; Menendez-Arias, Luis; Liu, Xinyong; Zhan, PengCurrent Medicinal Chemistry (2018), 25 (14), 1682-1702CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Combinations of antiretroviral drugs are successfully used to treat HIV-infected patients. However, drug resistance is a major problem that makes discovery of new antiretroviral drugs an ongoing priority. The RNase H (RNase H) activity of the HIV-1 reverse transcriptase catalyzes the selective hydrolysis of the RNA strand of RNA:DNA heteroduplex replication intermediates, and represents an attractive unexploited target for drug development. This review reports on recent progress in the characterization of HIV-1 RNase H inhibitors from 2013 to 2016, describing their chem. structures, structureactivity relationship and binding modes. Focus is given to emerging medicinal chem. principles and insights into the discovery and development of RNase H inhibitors.(d) Cao, L.; Song, W.; De Clercq, E.; Zhan, P.; Liu, X. Recent progress in the research of small molecule HIV-1 RNase H inhibitors. Curr. Med. Chem. 2014, 21, 1956– 1967, DOI: 10.2174/0929867321666140120121158[Crossref], [PubMed], [CAS], Google Scholar.74dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnt1emt78%253D&md5=b304a792478d2ffcbe8d85405c74f0c1Recent Progress in the Research of Small Molecule HIV-1 RNase H InhibitorsCao, Lili; Song, Weiguo; De Clercq, Erik; Zhan, Peng; Liu, XinyongCurrent Medicinal Chemistry (2014), 21 (17), 1956-1967CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Reverse transcription of human immunodeficiency virus type 1 (HIV-1) is a crucial step in the life cycle initiated by the viral-coded reverse transcriptase (RT), functioning as RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the RNase H (RNase H). The RNase H functions to degrade the RNA strand of the RNA:DNA heteroduplex, which makes it an attractive target for rational anti-HIV-1 drug design and development. Although development of drugs targeting the DNA polymerase have been highly successful, the discovery of drugable inhibitors of HIV RNase H is still in its infancy and none of RNase H inhibitors has reached the clin. development stage currently. This review describes the recent progress in the HIV-1 RNase H inhibitors, focusing on their chem. feature, mechanism and the structure-activity relationship (SAR).(e) Ju, H.; Zhang, J.; Huang, B.; Kang, D.; Huang, B.; Liu, X.; Zhan, P. Inhibitors of influenza virus polymerase acidic (PA) endonuclease: contemporary developments and perspectives. J. Med. Chem. 2017, 60, 3533– 3551, DOI: 10.1021/acs.jmedchem.6b01227[ACS Full Text.], [CAS], Google Scholar74ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFajs7Y%253D&md5=0432281c788ab6844753668e8208c3f6Inhibitors of Influenza Virus Polymerase Acidic (PA) Endonuclease: Contemporary Developments and PerspectivesJu, Han; Zhang, Jian; Huang, Boshi; Kang, Dongwei; Huang, Bing; Liu, Xinyong; Zhan, PengJournal of Medicinal Chemistry (2017), 60 (9), 3533-3551CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socio-economic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need to develop addnl. small-mol. inhibitors that act on IFV proteins. One promising target is polymerase acidic (PA) endonuclease, which is a bridged dinuclear metalloenzyme that plays a crucial role in initiating IFV replication. During the past decade, intensive efforts have been made to develop small-mol. inhibitors of this endonuclease as candidate agents for treatment of IFV infection. Here, the authors review the current status of development of PA endonuclease inhibitors and the authors discuss the applicability of newer medicinal-chem. strategies for the discovery more potent, selective, and safer inhibitors.(f) Ju, H.; Zhan, P.; Liu, X. Designing influenza polymerase acidic endonuclease inhibitors via ’privileged scaffold’ re-evolution/refining strategy. Future Med. Chem. 2019, 11, 265, DOI: 10.4155/fmc-2018-0489[Crossref], [CAS], Google Scholar74fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtlKhuro%253D&md5=4561c54e9850070aa333d4380cc0dbb9Designing influenza polymerase acidic endonuclease inhibitors via 'privileged scaffold' re-evolution/refining strategyJu, Han; Zhan, Peng; Liu, XinyongFuture Medicinal Chemistry (2019), 11 (4), 265-268CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review discussing the design of influenza polymerase acidic endonuclease inhibitors via privileged scaffold re-evolution/refining strategy.
- 75Yang, T. Baloxavir Marboxil: The first cap-dependent endonuclease inhibitor for the treatment of influenza. Ann. Pharmacother. 2019, 106002801982656, DOI: 10.1177/1060028019826565
- 76Oh, S.; Park, Y.; Engelhart, C. A.; Wallach, J. B.; Schnappinger, D.; Arora, K.; Manikkam, M.; Gac, B.; Wang, H.; Murgolo, N.; Olsen, D. B.; Goodwin, M.; Sutphin, M.; Weiner, D. M.; Via, L. E.; Boshoff, H. I. M.; Barry, C. E., 3rd. Discovery and structure-activity-relationship study of n-alkyl-5-hydroxypyrimidinone carboxamides as novel antitubercular agents targeting decaprenylphosphoryl-β-d-ribose 2′-oxidase. J. Med. Chem. 2018, 61, 9952– 9965, DOI: 10.1021/acs.jmedchem.8b00883[ACS Full Text], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2rsrfP&md5=5c8f50d73f857fcde7277ca80109fee9Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-D-ribose 2'-OxidaseOh, Sangmi; Park, Yumi; Engelhart, Curtis A.; Wallach, Joshua B.; Schnappinger, Dirk; Arora, Kriti; Manikkam, Michelle; Gac, Brian; Wang, Hongwu; Murgolo, Nicholas; Olsen, David B.; Goodwin, Michael; Sutphin, Michelle; Weiner, Danielle M.; Via, Laura E.; Boshoff, Helena I. M.; Barry, Clifton E.Journal of Medicinal Chemistry (2018), 61 (22), 9952-9965CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Magnesium plays an important role in infection with Mycobacterium tuberculosis (Mtb) as a signal of the extracellular environment, as a cofactor for many enzymes, and as a structural element in important macromols. Raltegravir, an antiretroviral drug that inhibits HIV-1 integrase is known to derive its potency from selective sequestration of active-site magnesium ions in addn. to binding to a hydrophobic pocket. In order to det. if essential Mtb-related phosphoryl transfers could be disrupted in a similar manner, a directed screen of known mols. with integrase inhibitor-like pharmacophores (N-alkyl-5-hydroxypyrimidinone carboxamides) was performed. Initial hits afforded compds. with low-micromolar potency against Mtb, acceptable cytotoxicity and PK characteristics, and robust SAR. Elucidation of the target of these compds. revealed that they lacked magnesium dependence and instead disappointingly inhibited a known promiscuous target in Mtb, decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1, Rv3790).
- 77Ramil, C. P.; Lin, Q. Bioorthogonal chemistry: strategies and recent developments. Chem. Commun. (Cambridge, U. K.) 2013, 49, 11007– 11022, DOI: 10.1039/c3cc44272a[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWls7vL&md5=55e8bcb626cf7d28ea9937a8fe800ca8Bioorthogonal chemistry: strategies and recent developmentsRamil, Carlo P.; Lin, QingChemical Communications (Cambridge, United Kingdom) (2013), 49 (94), 11007-11022CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. The use of covalent chem. to track biomols. in their native environment-a focus of bioorthogonal chem.-has received considerable interest recently among chem. biologists and org. chemists alike. To facilitate wider adoption of bioorthogonal chem. in biomedical research, a central effort in the last few years has been focused on the optimization of a few known bioorthogonal reactions, particularly with respect to reaction kinetics improvement, novel genetic encoding systems, and fluorogenic reactions for bioimaging. During these optimizations, three strategies have emerged, including the use of ring strain for substrate activation in the cycloaddn. reactions, the discovery of new ligands and privileged substrates for accelerated metal-catalyzed reactions, and the design of substrates with pre-fluorophore structures for rapid "turn-on" fluorescence after selective bioorthogonal reactions. In addn., new bioorthogonal reactions based on either modified or completely unprecedented reactant pairs have been reported. Finally, increasing attention has been directed toward the development of mutually exclusive bioorthogonal reactions and their applications in multiple labeling of a biomol. in cell culture. In this feature article, the authors wish to present the recent progress in bioorthogonal reactions through the selected examples that highlight the above-mentioned strategies. Considering increasing sophistication in bioorthogonal chem. development, the authors strive to project several exciting opportunities where bioorthogonal chem. can make a unique contribution to biol. in the near future.
- 78Kim, J.; Kim, H.; Park, S. B. Privileged structures: efficient chemical ″navigators″ toward unexplored biologically relevant chemical spaces. J. Am. Chem. Soc. 2014, 136, 14629– 14638, DOI: 10.1021/ja508343a[ACS Full Text], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsleksrjM&md5=27672b927e95b898a7f95cb0f2bd1ef8Privileged Structures: Efficient Chemical "Navigators" toward Unexplored Biologically Relevant Chemical SpacesKim, Jonghoon; Kim, Heejun; Park, Seung BumJournal of the American Chemical Society (2014), 136 (42), 14629-14638CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A review. In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally "undruggable" targets, and collections of drug-like small mols. with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chem. space with drug-like compds. contg. a high degree of mol. diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small mols. and therapeutic agents, and thus DOS has emerged as an essential tool in chem. biol. and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-mol. libraries with improved biol. relevancy as well as max. mol. diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compd. libraries with high biol. relevancy. We envisioned the specific interaction of drug-like small mols. with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small mols. and the subsequent identification of appropriate target biomol. using a method called "fluorescence difference in two-dimensional gel electrophoresis". Focusing on examples of pDOS-derived bioactive compds. with exceptional specificity, we discuss the capability of privileged structures to serve as chem. "navigators" toward biol. relevant chem. spaces. We also provide an outlook on chem. biol. research and drug discovery using biol. relevant compd. libraries constructed by pDOS, biol.-oriented synthesis, or natural product-inspired DOS.
- 79(a) Wang, X.; Huang, B.; Liu, X.; Zhan, P. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. Drug Discovery Today 2016, 21, 118– 132, DOI: 10.1016/j.drudis.2015.08.004[Crossref], [PubMed], [CAS], Google Scholar.79ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVOnt7%252FN&md5=57314fbcbf2e16e2267a8c9513a39b13Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial librariesWang, Xueshun; Huang, Boshi; Liu, Xinyong; Zhan, PengDrug Discovery Today (2016), 21 (1), 118-132CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chem. is a highly robust and efficient strategy for establishing SAR and for discovering bioactive mols. This review outlines the current status of this methodol. in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.(b) Huang, B.; Kang, D.; Zhan, P.; Liu, X. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities. Expert Opin. Drug Discovery 2015, 10, 1271– 1281, DOI: 10.1517/17460441.2015.1083007[Crossref], [PubMed], [CAS], Google Scholar.79bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFOmt7fK&md5=dc7627df6061a44e0595c1609094414dFragment-based approaches to anti-HIV drug discovery: state of the art and future opportunitiesHuang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, XinyongExpert Opinion on Drug Discovery (2015), 10 (12), 1271-1281CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)The search for addnl. drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this crit. review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophys. detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallog. overlays, fragment growth exploiting dynamic combinatorial chem., and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.(c) Gao, P.; Sun, L.; Zhou, J.; Li, X.; Zhan, P.; Liu, X. Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approach. Expert Opin. Drug Discovery 2016, 11, 857– 871, DOI: 10.1080/17460441.2016.1210125[Crossref], [PubMed], [CAS], Google Scholar79chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ejtbfK&md5=bfd4b8346b9b38bf68f3fcbba1f198b4Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approachGao, Ping; Sun, Lin; Zhou, Junsu; Li, Xiao; Zhan, Peng; Liu, XinyongExpert Opinion on Drug Discovery (2016), 11 (9), 857-871CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) click chem. approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants.: Herein, the authors describe the progress thus far on the discovery of novel anti-HIV agents via the CuAAC click chem.-based approach.: CuAAC click chem. is a proven protocol for synthesizing triazole products which could serve as basic pharmacophores, act as replacements of traditional scaffold or substituent modification, be a linker of dual-target or dual-site inhibitors and more for the discovery of novel anti-HIV agents. What's more, it also provides convenience and feasibility for dynamic combinatorial chem. and in situ screening. It is envisioned that click chem. will draw more attention and make more contributions in anti-HIV drug discovery in the future.
- 80Whiting, M.; Tripp, J. C.; Lin, Y. C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless, K. B.; Fokin, V. V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem. 2006, 49, 7697– 7710, DOI: 10.1021/jm060754+[ACS Full Text], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1GjsbjL&md5=252fb639055fb8e55a1e1a0eb0842853Rapid Discovery and Structure-Activity Profiling of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Protease Enabled by the Copper(I)-Catalyzed Synthesis of 1,2,3-Triazoles and Their Further FunctionalizationWhiting, Matthew; Tripp, Jonathan C.; Lin, Ying-Chuan; Lindstrom, William; Olson, Arthur J.; Elder, John H.; Sharpless, K. Barry; Fokin, Valery V.Journal of Medicinal Chemistry (2006), 49 (26), 7697-7710CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Building from the results of a computational screen of a range of triazole-contg. compds. for binding efficiency to human immunodeficiency virus type 1 protease (HIV-1-Pr), a novel series of potent inhibitors has been developed. The copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC), which provides ready access to 1,4-disubstituted-1,2,3-triazoles, was used to unite a focused library of azide-contg. fragments with a diverse array of functionalized alkyne-contg. building blocks. In combination with direct screening of the crude reaction products, this method led to the rapid identification of a lead structure and readily enabled optimization of both azide and alkyne fragments. Replacement of the triazole with a range of alternative linkers led to greatly reduced protease inhibition; however, further functionalization of the triazoles at the 5-position gave a series of compds. with increased activity, exhibiting Ki values as low as 8 nM.
- 81(a) Zhan, P.; Wang, X.; Liu, X.; Suzuki, T. Medicinal chemistry insights into novel HDAC inhibitors: an updated patent review (2012–2016). Recent Pat. Anti-Cancer Drug Discovery 2017, 12, 16– 34, DOI: 10.2174/1574892811666161101102842[Crossref], [PubMed], [CAS], Google Scholar.81ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1eqs7o%253D&md5=3b9f5e1eb3ad18be92e438952fb06efcMedicinal Chemistry Insights into Novel HDAC Inhibitors: An Updated Patent Review (2012-2016)Zhan, Peng; Wang, Xueshun; Liu, Xinyong; Suzuki, TakayoshiRecent Patents on Anti-Cancer Drug Discovery (2017), 12 (1), 16-34CODEN: RPADDY; ISSN:1574-8928. (Bentham Science Publishers Ltd.)A review. Background: Many labs. have made intensive efforts to develop potent, selective, and orally bioavailable HDAC inhibitors (HDACIs). Novel HDACIs are being developed with the objective of improving potency and selectivity against specific types of cancers or non-cancer diseases. Objective: This updated patent review is an attempt to compile the work of various researchers of HDACIs from 2012 to mid 2016, and to enlighten and surprise both newcomers in this field and devoted medicinal chemists. Method: According to the literature research and the writers' own research experience in the discovery of HDAC inhibitors. Results: The inhibitors possessing new chem. scaffolds have attracted immense interest because they have the ability to improve HDAC isoform specificity and pharmaceutical properties. Focus is given to emerging medicinal chem. principles and insights into the discovery and development of HDAC inhibitors. Conclusion: The development of effective HDACIs is shifting from trial-and-error approaches to sophisticated strategies. Effective profiling technologies will continue to have important utility.(b) Suzuki, T.; Ota, Y.; Ri, M.; Bando, M.; Gotoh, A.; Itoh, Y.; Tsumoto, H.; Tatum, P. R.; Mizukami, T.; Nakagawa, H.; Iida, S.; Ueda, R.; Shirahige, K.; Miyata, N. Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries. J. Med. Chem. 2012, 55, 9562– 9575, DOI: 10.1021/jm300837y[ACS Full Text.], [CAS], Google Scholar81bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsF2qtrfI&md5=9b730c0469b62c3ebd93a5e58c520a12Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate LibrariesSuzuki, Takayoshi; Ota, Yosuke; Ri, Masaki; Bando, Masashige; Gotoh, Aogu; Itoh, Yukihiro; Tsumoto, Hiroki; Tatum, Prima R.; Mizukami, Tamio; Nakagawa, Hidehiko; Iida, Shinsuke; Ueda, Ryuzo; Shirahige, Katsuhiko; Miyata, NaokiJournal of Medicinal Chemistry (2012), 55 (22), 9562-9575CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each contg. a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compds. were synthesized by using click chem. Screening identified HDAC8-selective inhibitors including (I) (IC50 = 0.070 μM), which was more potent than PCI-34058 (IC50 = 0.31 μM), a known HDAC8 inhibitor. Mol. modeling suggested that the phenylthiomethyl group of I binds to a unique hydrophobic pocket of HDAC8, and the orientation of the phenylthiomethyl and hydroxamate moieties (fixed by the triazole moiety) is important for the potency and selectivity. The inhibitors caused selective acetylation of cohesin in cells and exerted growth-inhibitory effects on T-cell lymphoma and neuroblastoma cells (GI50 = 3-80 μM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.(c) Suzuki, T.; Kasuya, Y.; Itoh, Y.; Ota, Y.; Zhan, P.; Asamitsu, K.; Nakagawa, H.; Okamoto, T.; Miyata, N. Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. PLoS One 2013, 8, e68669, DOI: 10.1371/journal.pone.0068669[Crossref], [PubMed], [CAS], Google Scholar.81chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SgsrjF&md5=74d12c8fb1f06f8e00691415434fd929Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assemblySuzuki, Takayoshi; Kasuya, Yuki; Itoh, Yukihiro; Ota, Yosuke; Zhan, Peng; Asamitsu, Kaori; Nakagawa, Hidehiko; Okamoto, Takashi; Miyata, NaokiPLoS One (2013), 8 (7), e68669CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chem.", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isoenzymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compds. showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isoenzymes. Compds. T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addn., these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chem. approach to find isoenzyme-selective HDAC inhibitors.(d) Tatum, P. R.; Sawada, H.; Ota, Y.; Itoh, Y.; Zhan, P.; Ieda, N.; Nakagawa, H.; Miyata, N.; Suzuki, T. Identification of novel SIRT2-selective inhibitors using a click chemistry approach. Bioorg. Med. Chem. Lett. 2014, 24, 1871– 1874, DOI: 10.1016/j.bmcl.2014.03.026[Crossref], [PubMed], [CAS], Google Scholar81dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltFKms7s%253D&md5=59676924d20f19655d23b39f4799769aIdentification of novel SIRT2-selective inhibitors using a click chemistry approachTatum, Prima R.; Sawada, Hideyuki; Ota, Yosuke; Itoh, Yukihiro; Zhan, Peng; Ieda, Naoya; Nakagawa, Hidehiko; Miyata, Naoki; Suzuki, TakayoshiBioorganic & Medicinal Chemistry Letters (2014), 24 (8), 1871-1874CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 114 SIRT inhibitor candidates was assembled using 'click chem.', by reacting two alkynes bearing 2-anilinobenzamide pharmacophore with 57 azide building blocks in the presence of Cu(I) catalyst. Screening identified two SIRT2-selective inhibitors, which were more SIRT2-selective than AGK2, a known SIRT2 inhibitor. These findings will be useful for further development of SIRT2-selective inhibitors.
- 82Gehringer, M.; Forster, M.; Laufer, S. A. Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition. ACS Comb. Sci. 2015, 17, 5– 10, DOI: 10.1021/co500122h[ACS Full Text], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCisbnI&md5=5d2999fedb2dfef332c2e860a9e376e4Solution-Phase Parallel Synthesis of Ruxolitinib-Derived Janus Kinase Inhibitors via Copper-Catalyzed Azide-Alkyne CycloadditionGehringer, Matthias; Forster, Michael; Laufer, Stefan A.ACS Combinatorial Science (2015), 17 (1), 5-10CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)A soln.-phase parallel synthesis of triazole-derived ruxolitinib analogs, e.g. I, was developed in the current study. The method employs copper-catalyzed azide-alkyne cycloaddn. to build up the central triazole template. Product isolation by pptn. and centrifugation is straightforward and yields high purity compds. suited for biol. profiling. A simple protocol for accessing the terminal alkyne precursors in high yields was established and a library of ruxolitinib-like triazoles featuring diverse functional groups was prepd. In addn., a model for the binding mode of ruxolitinib to Janus kinase (JAK) 2 is proposed. In contrast to previous models, the pose explains the compd. selectivity for JAK1/JAK2 and is in accordance with published structure-activity data. On this basis, a structure-based design hypothesis for inverting the selectivity profile of ruxolitinib is deduced. Application of this strategy identified a moderately potent JAK3 inhibitor (35 nM) with high selectivity against other JAKs, potentially exploiting a covalent binding mode.
- 83Diaz, L.; Casas, J.; Bujons, J.; Llebaria, A.; Delgado, A. New glucocerebrosidase inhibitors by exploration of chemical diversity of N-substituted aminocyclitols using click chemistry and in situ screening. J. Med. Chem. 2011, 54, 2069– 2079, DOI: 10.1021/jm101204u[ACS Full Text], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislGmtbw%253D&md5=f8dc841b74e119008201a1142cb7175aNew Glucocerebrosidase Inhibitors by Exploration of Chemical Diversity of N-Substituted Aminocyclitols Using Click Chemistry and in Situ ScreeningDiaz, Lucia; Casas, Josefina; Bujons, Jordi; Llebaria, Amadeu; Delgado, AntonioJournal of Medicinal Chemistry (2011), 54 (7), 2069-2079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A library of aminocyclitols, e.g. I, derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to phys. and reactivity constraints. A synthetic methodol. has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aq. system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually re-synthesized for further biol. screening and complete characterization. Some of the library members have shown biochem. data (IC50, Ki, and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand-enzyme interactions to account for the exptl. results.
- 84Coumar, M. S.; Chu, C. Y.; Lin, C. W.; Shiao, H. Y.; Ho, Y. L.; Reddy, R.; Lin, W. H.; Chen, C. H.; Peng, Y. H.; Leou, J. S.; Lien, T. W.; Huang, C. T.; Fang, M. Y.; Wu, S. H.; Wu, J. S.; Chittimalla, S. K.; Song, J. S.; Hsu, J. T.; Wu, S. Y.; Liao, C. C.; Chao, Y. S.; Hsieh, H. P. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. J. Med. Chem. 2010, 53, 4980– 4988, DOI: 10.1021/jm1000198[ACS Full Text], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsFyhs7s%253D&md5=8064e99d8d31603c7186b5fa33e019a6Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead IdentificationCoumar, Mohane Selvaraj; Chu, Chang-Ying; Lin, Cheng-Wei; Shiao, Hui-Yi; Ho, Yun-Lung; Reddy, Randheer; Lin, Wen-Hsing; Chen, Chun-Hwa; Peng, Yi-Hui; Leou, Jiun-Shyang; Lien, Tzu-Wen; Huang, Chin-Ting; Fang, Ming-Yu; Wu, Szu-Huei; Wu, Jian-Sung; Chittimalla, Santhosh Kumar; Song, Jen-Shin; Hsu, John T.-A.; Wu, Su-Ying; Liao, Chun-Chen; Chao, Yu-Sheng; Hsieh, Hsing-PangJournal of Medicinal Chemistry (2010), 53 (13), 4980-4988CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Furanopyrimidines such as I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4] are prepd. as Aurora A kinase and epidermal growth factor receptor (EGFR) inhibitors by prepn. of a combinatorial library of approx. 350 furanopyridines and optimization of the inhibitors found from the library. The initial hit compd. I (R = HOCH2CH2; R1 = Ph) was modified to better fit the back pocket to produce the potent Aurora A kinase inhibitor I (R = 4-PhNHCONHC6H4; R1 = Ph) with submicromolar antiproliferative activity in the HCT-116 human colon cancer cell line. On the basis of docking studies with EGFR hit I [R = (S)-HOCH2CHPh; R1 = Ph], introduction of an acrylamide Michael acceptor group led to I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4], which inhibited both the wild and mutant EGFR kinases and also showed antiproliferative activity in the gefitinib-resistant HCC827 human lung cancer cells. The X-ray cocrystal structures of I (R = HOCH2CH2, 4-PhNHCONHC6H4; R1 = Ph) bound to Aurora A kinase and the crystal structure of I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4] bound to EGFR confirmed their hypothesized binding modes.
- 85Ding, S.; Qiao, X.; Kucera, G. L.; Bierbach, U. Using a build-and-click approach for producing structural and functional diversity in DNA-targeted hybrid anticancer agents. J. Med. Chem. 2012, 55, 10198– 10203, DOI: 10.1021/jm301278c[ACS Full Text], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFamtr3E&md5=0ec806d4a18c7d19356f3384da200f92Using a Build-and-Click Approach for Producing Structural and Functional Diversity in DNA-Targeted Hybrid Anticancer AgentsDing, Song; Qiao, Xin; Kucera, Gregory L.; Bierbach, UlrichJournal of Medicinal Chemistry (2012), 55 (22), 10198-10203CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An efficient screening method was developed for functionalized DNA-targeted Pt-contg. hybrid anticancer agents based on metal-mediated amine-to-nitrile addn., a form of click chem. The goal of the study was to generate Pt-acridine agents for their use as cytotoxic warheads in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to Pt. The assay, which was based on microscale reactions between 6 Pt-nitrile complexes and 10 acridine derivs., yielded a small library of 60 Pt-acridines. Reactions were monitored, and product mixts. were quant. analyzed by automated in-line HPLC-electrospray mass spectrometry (LC-ESMS) anal. and subjected to cell viability screening (NCI-H460 cells) using a nonradioactive cell proliferation assay. The new prescreening methodol. proves to be a powerful tool for establishing structure-activity relations and for identifying target compds.
- 86Akgun, B.; Hall, D. G. Fast and tight boronate formation for click bioorthogonal conjugation. Angew. Chem., Int. Ed. 2016, 55, 3909– 3913, DOI: 10.1002/anie.201510321[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtlKgsLY%253D&md5=35b91b335c735d76e135ede920db1807Fast and Tight Boronate Formation for Click Bioorthogonal ConjugationAkgun, Burcin; Hall, Dennis G.Angewandte Chemie, International Edition (2016), 55 (12), 3909-3913CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A new click bioorthogonal reaction system was devised to enable the fast ligation (kON ≈ 340 M-1 s-1) of conjugatable derivs. of a rigid cyclic diol (nopoldiol) and a carefully optimized boronic acid partner, 2-methyl-5-carboxymethylphenylboronic acid. Using NMR and fluorescence spectroscopy studies, the corresponding boronates form reversibly within minutes at low micromolar concn. in water, providing submicromolar equil. const. (Keq≈105-106 M-1). Efficient protein conjugation under physiol. conditions was demonstrated with model proteins thioredoxin and albumin, and characterized by mass spectrometry and gel electrophoresis.
- 87Oueis, E.; Sabot, C.; Renard, P. Y. New insights into the kinetic target-guided synthesis of protein ligands. Chem. Commun. (Cambridge, U. K.) 2015, 51, 12158– 12169, DOI: 10.1039/C5CC04183J[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgtbbE&md5=76af69545c88c006feb0fe7a544b3805New insights into the kinetic target-guided synthesis of protein ligandsOueis, Emilia; Sabot, Cyrille; Renard, Pierre-YvesChemical Communications (Cambridge, United Kingdom) (2015), 51 (61), 12158-12169CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. The kinetic target-guided synthesis (KTGS) strategy is an unconventional discovery approach that takes advantage of the presence of the biol. target itself in order to irreversibly assemble the best inhibitors from an array of building blocks. This strategy has grown over the last two decades notably after the introduction of the in situ click chem. concept by Sharpless and colleagues in the early 2000s based on the use of the Huisgen cycloaddn. between terminal alkynes and azides. KTGS is a captivating area of research offering an unprecedented and powerful strategy to probe the macromol. complexity and dynamics of biol. targets. After a brief introduction listing all chem. ligation reactions reported to date in KTGS, this review focuses on the last five years' progress to expand the repertoire of the click or "click-like" tool box targeting proteins, as well as to overcome limitations arising in particular from false negatives, i.e. potent ligands that are not formed, or formed in undetectable trace amts. Furthermore, we wish to analyze the new twists and novelties described in some of these applications in order to better understand the conditions that govern this strategy and the extent to which it can be developed and generalized for a more efficient process.
- 88Frei, P.; Hevey, R.; Ernst, B. Dynamic combinatorial chemistry: A new methodology comes of age. Chemistry 2019, 25, 60, DOI: 10.1002/chem.201803365[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKqtL%252FF&md5=7943caf1b6063ab321b0543282c2e526Dynamic Combinatorial Chemistry: A New Methodology Comes of AgeFrei, Priska; Hevey, Rachel; Ernst, BeatChemistry - A European Journal (2019), 25 (1), 60-73CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Dynamic combinatorial chem. (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromol. targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodn. equil. However, upon addn. of a macromol. host which can bind and stabilize certain components of the library, the equil. compn. changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacol. relevant targets. Over time, the term tdDCC has been applied to describe a no. of different exptl. setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for anal. and evaluation of expts.
- 89Unver, M. Y.; Gierse, R. M.; Ritchie, H.; Hirsch, A. K. H. Druggability assessment of targets used in kinetic target-guided synthesis. J. Med. Chem. 2018, 61, 9395– 9409, DOI: 10.1021/acs.jmedchem.8b00266[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOmsLzO&md5=7f39f01bbc696d2f3bf27dc1d41c1bf4Druggability Assessment of Targets Used in Kinetic Target-Guided SynthesisUnver, M. Yagiz; Gierse, Robin M.; Ritchie, Harry; Hirsch, Anna K. H.Journal of Medicinal Chemistry (2018), 61 (21), 9395-9409CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biol. target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biol. target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, the authors performed a druggability assessment for each target family reported in KTGS, calcd. detailed information about the pocket properties and used them to search for possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall the authors conclude that the KTGS approach is universal and could be used without restrictions on the physicochem. properties of the addressed pocket.
- 90Hochgurtel, M.; Biesinger, R.; Kroth, H.; Piecha, D.; Hofmann, M. W.; Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev, A. V. Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological target. J. Med. Chem. 2003, 46, 356– 358, DOI: 10.1021/jm025589m[ACS Full Text], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252Fjtl2hsQ%253D%253D&md5=7f50c314bf5ee62b4c69c6c84fce6455Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological targetHochgurtel Matthias; Biesinger Ralf; Kroth Heiko; Piecha Dorothea; Hofmann Michael W; Krause Sonja; Schaaf Otmar; Nicolau Claude; Eliseev Alexey VJournal of medicinal chemistry (2003), 46 (3), 356-8 ISSN:0022-2623.New and potent inhibitors of neuraminidase, a key enzyme in the influenza virus activity, have been discovered in dynamic combinatorial libraries based on ketones and amines as building blocks. Selective synthesis of a number of inhibitors among multiple theoretically possible combinations of building blocks is driven by the presence of the target enzyme.
- 91Nasr, G.; Petit, E.; Vullo, D.; Winum, J. Y.; Supuran, C. T.; Barboiu, M. Carbonic anhydrase-encoded dynamic constitutional libraries: toward the discovery of isozyme-specific inhibitors. J. Med. Chem. 2009, 52, 4853– 4859, DOI: 10.1021/jm900449v[ACS Full Text], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotF2ruro%253D&md5=1f928d3994682815692e117881d6e6d0Carbonic Anhydrase-Encoded Dynamic Constitutional Libraries: Toward the Discovery of Isozyme-Specific InhibitorsNasr, Gihane; Petit, Eddy; Vullo, Daniela; Winum, Jean-Yves; Supuran, Claudiu T.; Barboiu, MihailJournal of Medicinal Chemistry (2009), 52 (15), 4853-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A constitutional dynamic library (CDL) was generated under thermodn. control by using the amino-carbonyl/imine interconversion as reversible chem., combined with noncovalent bonding within the active site of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Considering the pharmacol. importance to find isoform-selective CA inhibitors (CAIs), two of the 15 human (h) isoform, i.e., hCAI and hCA II, have been subjected to a parallel screening of the same CDL. The use of parallel constitutional screening of CDL chem. for the discovery of enzyme inhibitors is straightforward and it might provide initial insights toward the generation of efficient classes of selective, high affinity inhibitors. We demonstrate here that the high selectivity and specificity of inhibiting the hCA I and hCA II isoenzymes with some of the detected hits may be used to describe a complex constitutional behavior through component selection from the dynamic library, driven by the selective binding to the specific isoform active site. These results also point to the possibility of modulating the drug discovery methods by constitutional recomposition induced by a specific enzymic target.
- 92Bunyapaiboonsri, T.; Ramstrom, H.; Ramstrom, O.; Haiech, J.; Lehn, J. M. Generation of bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library. J. Med. Chem. 2003, 46, 5803– 5811, DOI: 10.1021/jm030917j[ACS Full Text], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1WqsbY%253D&md5=5bcf324bf322ee8b06ae430ffd6e725dGeneration of Bis-Cationic Heterocyclic Inhibitors of Bacillus subtilis HPr Kinase/Phosphatase from a Ditopic Dynamic Combinatorial LibraryBunyapaiboonsri, Taridaporn; Ramstroem, Helena; Ramstroem, Olof; Haiech, Jacques; Lehn, Jean-MarieJournal of Medicinal Chemistry (2003), 46 (26), 5803-5811CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ditopic dynamic combinatorial libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries contg. up to 440 different constituents. Of all possible acyl hydrazones formed, active compds. contg. two terminal cationic heterocyclic recognition groups sepd. by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-aminobenzimidazole, was identified from the process.
- 93Bhardwaj, A.; Kaur, J.; Wuest, M.; Wuest, F. In situ click chemistry generation of cyclooxygenase-2 inhibitors. Nat. Commun. 2017, 8, 1, DOI: 10.1038/s41467-016-0009-6[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWqt7fI&md5=32dc534437e3254fc9ce5f4839122d01In situ click chemistry generation of cyclooxygenase-2 inhibitorsBhardwaj, Atul; Kaur, Jatinder; Wuest, Melinda; Wuest, FrankNature Communications (2017), 8 (1), 1-14CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Cyclooxygenase-2 isoenzyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also assocd. with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isoenzyme can judiciously select most appropriate chem. building blocks from a pool of chems. to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chem., we describe the discovery of two highly potent and selective cyclooxygenase-2 isoenzyme inhibitors. The in vivo anti-inflammatory activity of these two novel small mols. is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
- 94Wang, Y.; Zhu, J.; Zhang, L. Discovery of cell-permeable O-GlcNAc transferase inhibitors via tethering in situ click chemistry. J. Med. Chem. 2017, 60, 263– 272, DOI: 10.1021/acs.jmedchem.6b01237[ACS Full Text], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFKksrnP&md5=eb17ed1f482911fef80c9f1fb80983daDiscovery of Cell-Permeable O-GlcNAc Transferase Inhibitors via Tethering in Situ Click ChemistryWang, Yue; Zhu, Jingjing; Zhang, LianwenJournal of Medicinal Chemistry (2017), 60 (1), 263-272CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic O-GlcNAcylation of nuclear and cytoplasmic proteins similar to phosphorylation. Discovery of cell-permeable OGT inhibitors is significant to clarify the function and regulatory mechanism of O-GlcNAcylation. This will establish the foundation for the development of therapeutic drugs for relevant diseases. Here, the authors report two cell-permeable OGT inhibitors (APNT and APBT), developed from low-activity precursors (IC50 > 1 mM) via "tethering in situ click chem. (TISCC)". Both of them were able to inhibit O-GlcNAcylation in cells without significant effects on cell viability. Unusual noncompetitive inhibition of OGT was helpful to discover novel inhibitors and explore the regulatory mechanism of OGT. The development of these mols. validates that TISCC can be utilized to discover novel lead compds. from components which exhibited very weak binding to the target.
- 95Namelikonda, N. K.; Manetsch, R. Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesis. Chem. Commun. (Cambridge, U. K.) 2012, 48, 1526– 1528, DOI: 10.1039/C1CC14724B[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtF2hsg%253D%253D&md5=70d29deebe58911e0f98e272c2650730Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesisNamelikonda, Niranjan Kumar; Manetsch, RomanChemical Communications (Cambridge, United Kingdom) (2012), 48 (10), 1526-1528CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A practical, one-pot variant of the sulfo-click reaction was described, in which 9-fluorenylmethyl-protected thioesters are rapidly deprotected and reacted further with sulfonylazides to give N-acyl sulfonamides, e.g. I.
- 96Kulkarni, S. S.; Hu, X.; Doi, K.; Wang, H. G.; Manetsch, R. Screening of protein-protein interaction modulators via sulfo-click kinetic target-guided synthesis. ACS Chem. Biol. 2011, 6, 724– 732, DOI: 10.1021/cb200085q[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsFyqt7Y%253D&md5=c57b60a88631ce37bd5dbeaa3b2e2f35Screening of Protein-Protein Interaction Modulators via Sulfo-Click Kinetic Target-Guided SynthesisKulkarni, Sameer S.; Hu, Xiangdong; Doi, Kenichiro; Wang, Hong-Gang; Manetsch, RomanACS Chemical Biology (2011), 6 (7), 724-732CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Kinetic target-guided synthesis (TGS) and in situ click chem. are among unconventional discovery strategies having the potential to streamline the development of protein-protein interaction modulators (PPIMs). In kinetic TGS and in situ click chem., the target is directly involved in the assembly of its own potent, bidentate ligand from a pool of reactive fragments. Herein, we report the use and validation of kinetic TGS based on the sulfo-click reaction between thio acids and sulfonyl azides as a screening and synthesis platform for the identification of high-quality PPIMs. Starting from a randomly designed library consisting of 9 thio acids and 9 sulfonyl azides leading to 81 potential acylsulfonamides, the target protein, Bcl-XL, selectively assembled four PPIMs, acylsulfonamides SZ4TA2, SZ7TA2, SZ9TA1, and SZ9TA5, which have been shown to modulate Bcl-XL/BH3 interactions. To further investigate the Bcl-XL templation effect, control expts. were carried out using two mutants of Bcl-XL. In one mutant, phenylalanine Phe131 and aspartic acid Asp133, which are crit. for the BH3 domain binding, were substituted by alanines, while arginine Arg139, a residue identified to play a crucial role in the binding of ABT-737, a BH3 mimetic, was replaced by an alanine in the other mutant. Incubation of these mutants with the reactive fragments and subsequent LC/MS-SIM anal. confirmed that these building block combinations yield the corresponding acylsulfonamides at the BH3 binding site, the actual "hot spot" of Bcl-XL. These results validate kinetic TGS using the sulfo-click reaction as a valuable tool for the straightforward identification of high-quality PPIMs.
- 97Antti, H.; Sellstedt, M. Cell-based kinetic target-guided synthesis of an enzyme Inhibitor. ACS Med. Chem. Lett. 2018, 9, 351– 353, DOI: 10.1021/acsmedchemlett.7b00535[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFansr8%253D&md5=117e4a2748228d419128f2d2046c2e35Cell-Based Kinetic Target-Guided Synthesis of an Enzyme InhibitorAntti, Henrik; Sellstedt, MagnusACS Medicinal Chemistry Letters (2018), 9 (4), 351-353CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Finding a new drug candidate for a selected target is an expensive and time-consuming process. Target guided-synthesis, or in situ click chem., is a concept where the drug target is used to template the formation of its own inhibitors from reactive building blocks. This could simplify the identification of drug candidates. However, with the exception of one example of an RNA-target, target-guided synthesis has always employed purified targets. This limits the no. of targets that can be screened by the method. By applying methods from the field of metabolomics, we demonstrate that target-guided synthesis with protein targets also can be performed directly in cell-based systems. These methods offer new possibilities to conduct screening for drug candidates of difficult protein targets in cellular environments.
- 98Lebraud, H.; Wright, D. J.; Johnson, C. N.; Heightman, T. D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent. Sci. 2016, 2, 927– 934, DOI: 10.1021/acscentsci.6b00280[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFOltbbJ&md5=4cc9b4aaba6ee03cd2d4ea97a72728a5Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting ChimerasLebraud, Honorine; Wright, David J.; Johnson, Christopher N.; Heightman, Tom D.ACS Central Science (2016), 2 (12), 927-934CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Selective degrdn. of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC mols. incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional mols. require significant linker optimization and possess high mol. wt., which can limit cellular permeation, soly., and other drug-like properties. We show here that the hetero-bifunctional mol. can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide deriv. which reacts rapidly with a trans-cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC mol. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncol. targets, BRD4 and ERK1/2. ERK1/2 degrdn. was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degrdn.
- 99(a) Sindelar, M.; Wanner, K. T. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1). ChemMedChem 2012, 7, 1678– 1690, DOI: 10.1002/cmdc.201200201[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot1Khu7c%253D&md5=98216d9b84dca9be3dd0b34fe4602461Library Screening by Means of Mass Spectrometry (MS) Binding Assays-Exemplarily Demonstrated for a Pseudostatic Library Addressing γ-Aminobutyric Acid (GABA) Transporter 1 (GAT1)Sindelar, Miriam; Wanner, Klaus T.ChemMedChem (2012), 7 (9), 1678-1690, S1678/1-S1678/7CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)In the present study, the application of mass spectrometry (MS) binding assays as a tool for library screening is reported. For library generation, dynamic combinatorial chem. (DCC) was used. These libraries can be screened by MS binding assays when appropriate measures are taken to render the libraries pseudostatic. That way, the efficiency of MS binding assays to det. ligand binding in compd. screening with the ease of library generation by DCC is combined. The feasibility of this approach is shown for γ-aminobutyric acid (GABA) transporter 1 (GAT1) as a target, representing the most important subtype of the GABA transporters. For the screening, hydrazone libraries were employed that were generated in the presence of the target by reacting various sets of aldehydes with a hydrazine deriv. that is delineated from piperidine-3-carboxylic acid (nipecotic acid), a common fragment of known GAT1 inhibitors. To ensure that the library generated is pseudostatic, a large excess of the nipecotic acid deriv. is employed. As the library is generated in a buffer system suitable for binding and the target is already present, the mixts. can be directly analyzed by MS binding assays-the process of library generation and screening thus becoming simple to perform. The binding affinities of the hits identified by deconvolution were confirmed in conventional competitive MS binding assays performed with single compds. obtained by sep. synthesis. In this way, two nipecotic acid derivs. exhibiting a biaryl moiety, 1-{2-[2'-(1,1'-biphenyl-2-ylmethylidene)hydrazine]ethyl}piperidine-3-carboxylic acid and 1-(2-{2'-[1-(2-thiophenylphenyl)methylidene]hydrazine}ethyl)piperidine-3-carboxylic acid, were potent GAT1 ligands exhibiting pKi values of 6.186±0.028 and 6.229±0.039, resp. This method enables screening of libraries, whether generated by conventional chem. or DCC, and is applicable to all kinds of targets including membrane-bound targets such as G protein coupled receptors (GPCRs), ion channels and transporters. As such, this strategy displays high potential in the drug discovery process.(b) Sindelar, M.; Lutz, T. A.; Petrera, M.; Wanner, K. T. Focused pseudostatic hydrazone libraries screened by mass spectrometry binding assay: optimizing affinities toward γ-aminobutyric acid transporter 1. J. Med. Chem. 2013, 56, 1323– 1340, DOI: 10.1021/jm301800j[ACS Full Text.], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCns7g%253D&md5=747ff650d39eaa3a01dedfdac7058191Focused Pseudostatic Hydrazone Libraries Screened by Mass Spectrometry Binding Assay: Optimizing Affinities toward γ-Aminobutyric Acid Transporter 1Sindelar, Miriam; Lutz, Toni A.; Petrera, Marilena; Wanner, Klaus T.Journal of Medicinal Chemistry (2013), 56 (3), 1323-1340CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mass spectrometric (MS) binding assays, a powerful tool to det. affinities of single drug candidates toward chosen targets, were recently demonstrated to be suitable for the screening of compd. libraries generated with reactions of dynamic combinatorial chem. when rendering libraries pseudostatic. Screening of small hydrazone libraries targeting γ-aminobutyric acid transporter 1 (GAT1), the most abundant γ-aminobutyric acid (GABA) transporter in the central nervous system, revealed two nipecotic acid derived binders with submicromolar affinities. Starting from the biphenyl carrying hit as lead structure, the objective of the present study was to discover novel high affinity GAT1 binders by screening of biphenyl focused pseudo-static hydrazone libraries formed from hydrazine (I) and 36 biphenylcarbaldehydes. Hydrazone (II) that carried a 2',4'-dichlorobiphenyl residue was found to be the most potent binder with low nanomolar affinity (pKi = 8.094±0.098). When stable carba analogs of representative hydrazones were synthesized and evaluated, the best binder 13z was again displaying the 2',4'-dichlorobiphenyl moiety (pKi = 6.930±0.021).(c) Hauke, T. J.; Wein, T.; Höfner, G.; Wanner, K. T. Novel allosteric ligands of γ-aminobutyric acid transporter 1 (GAT1) by MS based screening of pseudostatic hydrazone libraries. J. Med. Chem. 2018, 61, 10310– 10332, DOI: 10.1021/acs.jmedchem.8b01602[ACS Full Text.], [CAS], Google Scholar99chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCisLbJ&md5=c7cad956702acfe6d59dea0c2faa14cdNovel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone LibrariesHauke, Tobias J.; Wein, Thomas; Hoefner, Georg; Wanner, Klaus T.Journal of Medicinal Chemistry (2018), 61 (22), 10310-10332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compds. and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured compd. I bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake expts. revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid deriv. up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivs. could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.(d) Huber, S. K.; Höfner, G.; Wanner, K. T. Identification of pyrrolidine-3-acetic acid derived oximes as potent inhibitors of γ-aminobutyric acid transporter 1 through library screening with MS binding assays. ChemMedChem 2018, 13, 2488– 2503, DOI: 10.1002/cmdc.201800556[Crossref], [PubMed], [CAS], Google Scholar99dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlentr%252FE&md5=ca9cb3a556ebe7a2b699ce3fc86a4bf8Identification of Pyrrolidine-3-acetic Acid Derived Oximes as Potent Inhibitors of γ-Aminobutyric Acid Transporter 1 through Library Screening with MS Binding AssaysHuber, Simone K.; Hoefner, Georg; Wanner, Klaus T.ChemMedChem (2018), 13 (23), 2488-2503CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution expts. to identify single oximes responsible for the obsd. activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine-3-acetic acid motif were found, of which the most potent oxime, possessing a 2',4'-dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi=7.87±0.01).
- 100(a) Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; Yeoh, K. K.; Tian, Y.-M.; Claridge, T. D. W.; Rgatcliffe, P. J.; Woon, E. C. Y.; Schofield, C. J. Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors. Angew. Chem., Int. Ed. 2012, 51, 6672– 6675, DOI: 10.1002/anie.201202000[Crossref], [CAS], Google Scholar.100ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1WjtL0%253D&md5=1e6b2d573dec343072822882f9cccaefDynamic Combinatorial Chemistry Employing Boronic Acids/Boronate Esters Leads to Potent Oxygenase InhibitorsDemetriades, Marina; Leung, Ivanhoe K. H.; Chowdhury, Rasheduzzaman; Chan, Mun Chiang; McDonough, Michael A.; Yeoh, Kar Kheng; Tian, Ya-Min; Claridge, Timothy D. W.; Ratcliffe, Peter J.; Woon, Esther C. Y.; Schofield, Christopher J.Angewandte Chemie, International Edition (2012), 51 (27), 6672-6675, S6672/1-S6672/53CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The reversible reaction of boronic acids with alcs. to form boronate esters, coupled to protein mass spectrometry analyses, was used to discover potent oxygenase inhibitors. This dynamic combinatorial mass spectrometry technique could potentially be applied to the identification of other protein inhibitors.(b) Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L.; Aik, W. S.; Krylova, S. M.; Ma, J. H. Y.; Chan, M. C.; Walport, L. J.; Wegman, D. W.; Dack, K. N.; McDonough, M. A.; Krylov, S. N.; Schofield, C. J. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate dependent nucleic acid demethylase. J. Med. Chem. 2012, 55, 2173– 2184, DOI: 10.1021/jm201417e[ACS Full Text.], [CAS], Google Scholar100bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymur0%253D&md5=a7e7f3fae71f6764ce34ac1d5737cffcDynamic Combinatorial Mass Spectrometry Leads to Inhibitors of a 2-Oxoglutarate-Dependent Nucleic Acid DemethylaseWoon, Esther C. Y.; Demetriades, Marina; Bagg, Eleanor A. L.; Aik, WeiShen; Krylova, Svetlana M.; Ma, Jerome H. Y.; Chan, MunChiang; Walport, Louise J.; Wegman, David W.; Dack, Kevin N.; McDonough, Michael A.; Krylov, Sergey N.; Schofield, Christopher J.Journal of Medicinal Chemistry (2012), 55 (5), 2173-2184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)2-Oxoglutarate-dependent nucleic acid demethylases are of biol. interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiol., their regulatory roles are unclear. Hence, there is a desire to develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable to selective inhibition by small mols. Dynamic combinatorial chem. linked to mass spectrometric analyses (DCMS) led to the identification of lead compds., one of which was analyzed by crystallog. Subsequent structure-guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.(c) Rose, N. R.; Woon, E. C. Y.; Kingham, G. L.; King, O. N. F.; Mecinovic, J.; Clifton, I. J.; Ng, S. S.; Talib-Hardy, J.; Oppermann, U.; McDonough, M. A.; Schofield, C. J. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. J. Med. Chem. 2010, 53, 1810– 1818, DOI: 10.1021/jm901680b[ACS Full Text], [CAS], Google Scholar100chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFWnsQ%253D%253D&md5=3eb3c36d91f46193946f64288ea9ccaeSelective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic ApproachesRose, Nathan R.; Woon, Esther C. Y.; Kingham, Guy L.; King, Oliver N. F.; Mecinovic, Jasmin; Clifton, Ian J.; Ng, Stanley S.; Talib-Hardy, Jobina; Oppermann, Udo; McDonough, Michael A.; Schofield, Christopher J.Journal of Medicinal Chemistry (2010), 53 (4), 1810-1818CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of Nε-methylated lysine residues in histones. Here, studies on the inhibition of the JMJD2 subfamily of histone demethylases are reported, employing binding analyses by non-denaturing mass spectrometry (MS), dynamic combinatorial chem. coupled to MS, turnover assays, and crystallog. The results of initial binding and inhibition assays directed the prodn. and anal. of a set of N-oxalyl-D-tyrosine derivs. to explore the extent of a sub-pocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compds.
- 101Das, M.; Tianming, Y.; Jinghua, D.; Prasetya, F.; Yiming, X.; Wong, K.; Cheong, A.; Woon, E. C. Y. Multi-protein dynamic combinatorial chemistry: a novel strategy that leads to simultaneous discovery of subfamily-selective inhibitors for nucleic acid demethylases FTO and ALKBH3. Chem. Asian J. 2018, 13, 2854, DOI: 10.1002/asia.201800729[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaiu7%252FK&md5=2e8dca74858c93f2cbf8f77b9cb5660dMultiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3Das, Mohua; Yang, Tianming; Dong, Jinghua; Prasetya, Fransisca; Xie, Yiming; Wong, Kendra H. Q.; Cheong, Adeline; Woon, Esther C. Y.Chemistry - An Asian Journal (2018), 13 (19), 2854-2867CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)Dynamic combinatorial chem. (DCC) is a powerful supramol. approach for discovering ligands for biomols. To date, most, if not all, biol. templated DCC systems employ only a single biomol. to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic "thermal tag" with the sensitivity of differential scanning fluorimetry (DSF). This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clin. important epigenetic enzymes: FTO (7; IC50 = 2.6 μm) and ALKBH3 (8; IC50 = 3.7 μm). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.
- 102Jana, S.; Panda, D.; Saha, P.; Pantos, D.; Dash, J. Dynamic generation of G-quadruplex DNA ligands by target-guided combinatorial chemistry on a magnetic nano-platform. J. Med. Chem. 2019, 62, 762, DOI: 10.1021/acs.jmedchem.8b01459[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKrsLvK&md5=af30b67c78bee38c1bcc5b71341bdd31Dynamic Generation of G-Quadruplex DNA Ligands by Target-Guided Combinatorial Chemistry on a Magnetic NanoplatformJana, Snehasish; Panda, Deepanjan; Saha, Puja; Pantos, G. Dan; Dash, JyotirmayeeJournal of Medicinal Chemistry (2019), 62 (2), 762-773CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dynamic combinatorial chem. (DCC) has emerged as a promising strategy for template-driven selection of high-affinity ligands for biol. targets from equilibrating combinatorial libraries. However, only a few examples using disulfide-exchange-based DCC are reported for nucleic acid targets. Herein, gold-coated magnetic nanoparticle-conjugated DNA targets can be used as templates for dynamic selection of ligands from an imine-based combinatorial library. The implementation of DCC using DNA nanotemplates enables efficient identification of the lead compds., from the dynamic combinatorial library via magnetic decantation. It further allows quick sepn. of DNA nanotemplates for reuse in DCC reactions. The identified lead compd. exhibits significant quadruplex vs. duplex DNA selectivity and suppresses promoter activity of c-MYC gene that contains G-quadruplex DNA forming sequence in the upstream promoter region. Further cellular expts. indicated that the lead compd. is able to permeate into cell nuclei and trigger a DNA damage response in cancer cells.
- 103Tu, J.; Xu, M.; Franzini, R. Dissociative bioorthogonal reactions. ChemBioChem 2019, DOI: 10.1002/cbic.201800810
- 104Li, J.; Chen, P. R. Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat. Chem. Biol. 2016, 12, 129– 137, DOI: 10.1038/nchembio.2024[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVCis74%253D&md5=6b563f0c618e43f97bf4cea26c060451Development and application of bond cleavage reactions in bioorthogonal chemistryLi, Jie; Chen, Peng R.Nature Chemical Biology (2016), 12 (3), 129-137CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)A review. Bioorthogonal chem. reactions are a thriving area of chem. research in recent years as an unprecedented technique to dissect native biol. processes through chem.-enabled strategies. However, current concepts of bioorthogonal chem. have largely centered on bond formation reactions between two mutually reactive bioorthogonal handles. Recently, in a reverse strategy, a collection of bond cleavage reactions has emerged with excellent biocompatibility. These reactions have expanded the bioorthogonal chem. repertoire, enabling an array of exciting new biol. applications that range from the chem. controlled spatial and temporal activation of intracellular proteins and small-mol. drugs to the direct manipulation of intact cells under physiol. conditions. Here the authors highlight the development and applications of these bioorthogonal cleavage reactions. Furthermore, the authors lay out challenges and propose future directions along this appealing avenue of research.
- 105(a) Unciti-Broceta, A.; Johansson, E. M.; Yusop, R. M.; Sanchez-Martin, R. M.; Bradley, M. Synthesis of polystyrene microspheres and functionalization with Pd(0) nanoparticles to perform bioorthogonal organometallic chemistry in living cells. Nat. Protoc. 2012, 7, 1207– 1218, DOI: 10.1038/nprot.2012.052[Crossref], [PubMed], [CAS], Google Scholar.105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnslSmur8%253D&md5=7ab4fa74d57436f77bb70646bf15a794Synthesis of polystyrene microspheres and functionalization with Pd0 nanoparticles to perform bioorthogonal organometallic chemistry in living cellsUnciti-Broceta, Asier; Johansson, Emma M. V.; Yusop, Rahimi M.; Sanchez-Martin, Rosario M.; Bradley, MarkNature Protocols (2012), 7 (6), 1207-1218CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)We have developed miniaturized heterogeneous Pd0-catalysts (Pd0-microspheres) with the ability to enter cells, stay harmlessly within the cytosol and mediate efficient bioorthogonal organometallic chemistries (e.g., allylcarbamate cleavage and Suzuki-Miyaura cross-coupling). This approach is a major addn. to the toolbox available for performing chem. reactions within cells. Here we describe a full protocol for the synthesis of the Pd0-microspheres from readily available starting materials (by the synthesis of size-controlled amino-functionalized polystyrene microspheres), as well as for their characterization (electron microscopy and palladium quantitation) and functional validation ('in soln.' and 'in cytoplasm' conversions). From the beginning of the synthesis to functional evaluation of the catalytic device requires 5 d of work.(b) Yusop, R. M.; Unciti-Broceta, A.; Johansson, E. M.; Sanchez-Martin, R. M.; Bradley, M. Palladium-mediated intracellular chemistry. Nat. Chem. 2011, 3, 239– 243, DOI: 10.1038/nchem.981[Crossref], [PubMed], [CAS], Google Scholar.105bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Wru7s%253D&md5=f6011d340f1d5666475190a2a66b3313Palladium-mediated intracellular chemistryYusop, Rahimi M.; Unciti-Broceta, Asier; Johansson, Emma M. V.; Sanchez-Martin, Rosario M.; Bradley, MarkNature Chemistry (2011), 3 (3), 239-243CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Many important intracellular biochem. reactions are modulated by transition metals, typically in the form of metalloproteins. The ability to carry out selective transformations inside a cell would allow researchers to manipulate or interrogate innumerable biol. processes. Here, we show that palladium nanoparticles trapped within polystyrene microspheres can enter cells and mediate a variety of Pd0-catalyzed reactions, such as allylcarbamate cleavage and Suzuki-Miyaura cross-coupling. The work provides the basis for the customization of heterogeneous unnatural catalysts as tools to carry out artificial chemistries within cells. Such in cellular synthesis has potential for a plethora of applications ranging from cellular labeling to synthesis of modulators or inhibitors of cell function.(c) Unciti-Broceta, A. Bioorthogonal catalysis: Rise of the nanobots. Nat. Chem. 2015, 7, 538– 539, DOI: 10.1038/nchem.2291[Crossref], [PubMed], [CAS], Google Scholar.105chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yjs7%252FK&md5=2feca0ef4c0b075240520c65f83540f8Bioorthogonal catalysis Rise of the nanobotsUnciti-Broceta, AsierNature Chemistry (2015), 7 (7), 538-539CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Bioorthogonal catalysis provides new ways of mediating artificial transformations in living environs. Now, researchers have developed a nanodevice whose catalytic activity can be regulated by host-guest chem.(d) Weiss, J. T.; Dawson, J. C.; Fraser, C.; Rybski, W.; Torres-Sanchez, C.; Bradley, M.; Patton, E. E.; Carragher, N. O.; Unciti-Broceta, A. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine. J. Med. Chem. 2014, 57, 5395– 5404, DOI: 10.1021/jm500531z[ACS Full Text.], [CAS], Google Scholar105dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1ajs7c%253D&md5=2d354f262acebde27b4d1345fe0175b6Development and Bio-Orthogonal Activation of Palladium-Labile Prodrugs of GemcitabineWeiss, Jason T.; Dawson, John C.; Fraser, Craig; Rybski, Witold; Torres-Sanchez, Carmen; Bradley, Mark; Patton, E. Elizabeth; Carragher, Neil O.; Unciti-Broceta, AsierJournal of Medicinal Chemistry (2014), 57 (12), 5395-5404CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bio-orthogonal chem. has become one of the main driving forces in current chem. biol., inspiring the search for novel bio-compatible chemo-specific reactions for the past decade. Alongside the well-established labeling strategies that originated the bio-orthogonal paradigm, we have recently proposed the use of heterogeneous palladium chem. and bio-orthogonal Pd0-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biol. inert precursors of cytotoxic gemcitabine by introducing Pd0-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacol. activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced ( > 23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) moiety displayed the highest sensitivity to heterogeneous palladium catalysis under bio-compatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bio-orthogonal organo-metallic chem.(e) Weiss, J. T.; Dawson, J. C.; Macleod, K. G.; Rybski, W.; Fraser, C.; Torres-Sanchez, C.; Patton, E. E.; Bradley, M.; Carragher, N. O.; Unciti-Broceta, A. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Commun. 2014, 5, 3277, DOI: 10.1038/ncomms4277[Crossref], [PubMed], [CAS], Google Scholar.105ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvkslGhtw%253D%253D&md5=0eea3d70b9d493cad2223e5d3ca87514Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approachWeiss Jason T; Dawson John C; Macleod Kenneth G; Fraser Craig; Carragher Neil O; Unciti-Broceta Asier; Rybski Witold; Patton E Elizabeth; Torres-Sanchez Carmen; Bradley MarkNature communications (2014), 5 (), 3277 ISSN:.A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.(f) Weiss, J. T.; Fraser, C.; Rubio-Ruiz, B.; Myers, S. H.; Crispin, R.; Dawson, J. C.; Brunton, V. G.; Patton, E. E.; Carragher, N. O.; Unciti-Broceta, A. N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture. Front Chem. 2014, 2, 56, DOI: 10.3389/fchem.2014.00056[Crossref], [PubMed], [CAS], Google Scholar.105fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fhs1Gktw%253D%253D&md5=767f9b4f959fef7c4a558cb373571de6N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell cultureWeiss Jason T; Fraser Craig; Rubio-Ruiz Belen; Myers Samuel H; Dawson John C; Brunton Valerie G; Carragher Neil O; Unciti-Broceta Asier; Crispin Richard; Patton E ElizabethFrontiers in chemistry (2014), 2 (), 56 ISSN:2296-2646.Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd(0), has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug's cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug's pharmacological activity in the presence of extracellular Pd(0)-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- vs. the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug), whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture.(g) Weiss, J. T.; Carragher, N. O.; Unciti-Broceta, A. Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy. Sci. Rep. 2015, 5, 9329, DOI: 10.1038/srep09329[Crossref], [PubMed], [CAS], Google Scholar.105ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFKku7rM&md5=f962ebb91e375e44756ae19e6596e275Palladium-Mediated Dealkylation of N-Propargyl-Floxuridine as a Bioorthogonal Oxygen-Independent Prodrug StrategyWeiss, Jason T.; Carragher, Neil O.; Unciti-Broceta, AsierScientific Reports (2015), 5 (), 9329CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Herein we report the development and biol. screening of a bioorthogonal palladium-labile prodrug of the nucleoside analog floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast redn. of its biol. activity (∼6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chem. both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy.(h) Rubio-Ruiz, B.; Weiss, J. T.; Unciti-Broceta, A. Efficient palladium-triggered release of vorinostat from a bioorthogonal precursor. J. Med. Chem. 2016, 59, 9974– 9980, DOI: 10.1021/acs.jmedchem.6b01426[ACS Full Text], [CAS], Google Scholar105hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGht7fL&md5=0549af63fb54dd8135a81b374939f59dEfficient Palladium-Triggered Release of Vorinostat from a Bioorthogonal PrecursorRubio-Ruiz, Belen; Weiss, Jason T.; Unciti-Broceta, AsierJournal of Medicinal Chemistry (2016), 59 (21), 9974-9980CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bioorthogonal uncaging strategies have recently emerged as an exptl. therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chem. using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer.
- 106Lv, T.; Wu, J.; Kang, F.; Wang, T.; Wan, B.; Lu, J. J.; Zhang, Y.; Huang, Z. Synthesis and evaluation of O(2)-derived diazeniumdiolates activatable via bioorthogonal chemistry reactions in living cells. Org. Lett. 2018, 20, 2164– 2167, DOI: 10.1021/acs.orglett.8b00423[ACS Full Text], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmt1Cns74%253D&md5=135a8b5f46dc617e211b6d32b93c462cSynthesis and Evaluation of O2-Derived Diazeniumdiolates Activatable via Bioorthogonal Chemistry Reactions in Living CellsLv, Tian; Wu, Jianbing; Kang, Fenghua; Wang, Tingting; Wan, Boheng; Lu, Jin-Jian; Zhang, Yihua; Huang, ZhangjianOrganic Letters (2018), 20 (8), 2164-2167CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A class of O2-alkyl derived diazeniumdiolates R1R2NN(O-):N+OCH2C≡CH (NR1R2 = pyrrolidino, 4-methylpiperazino, morpholino, diethylamino, 2-hydroxyethylamino), R1R2NN(O-):N+OCH2CH:CH2 (R1R2N = pyrrolidino) and I (R = CH2C≡CH, CH2CH:CH2, C:C:CH2) were designed and synthesized as new bioorthogonal NO precursors, which can be effectively uncaged in the presence of a palladium catalyst via bioorthogonal bond cleavage reactions to generate NO in living cancer cells, eliciting potent antiproliferative activity.
- 107Li, J.; Jia, S.; Chen, P. R. Diels-Alder reaction-triggered bioorthogonal protein decaging in living cells. Nat. Chem. Biol. 2014, 10, 1003– 1005, DOI: 10.1038/nchembio.1656[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGiurfM&md5=4723cef7d02aec13267b61d08c9517a6Diels-Alder reaction-triggered bioorthogonal protein decaging in living cellsLi, Jie; Jia, Shang; Chen, Peng R.Nature Chemical Biology (2014), 10 (12), 1003-1005CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Small mols. that specifically activate an intracellular protein of interest are highly desirable. A generally applicable strategy, however, remains elusive. Herein we describe a small mol.-triggered bioorthogonal protein decaging technique that relies on the inverse electron-demand Diels-Alder reaction for eliminating a chem. caged protein side chain within living cells. This method permits the efficient activation of a given protein (for example, an enzyme) in its native cellular context within minutes.
- 108Perez-Lopez, A. M.; Rubio-Ruiz, B.; Sebastián, V.; Hamilton, L.; Adam, C.; Bray, T. L.; Irusta, S.; Brennan, P. M.; Lloyd-Jones, G. C.; Sieger, D.; Santamaría, J.; Unciti-Broceta, A. Gold-triggered uncaging chemistry in living systems. Angew. Chem., Int. Ed. 2017, 56, 12548– 12552, DOI: 10.1002/anie.201705609[Crossref], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlSmur%252FF&md5=34046f0a80e09abd4dc6e8f8b5f39584Gold-Triggered Uncaging Chemistry in Living SystemsPerez-Lopez, Ana M.; Rubio-Ruiz, Belen; Sebastian, Victor; Hamilton, Lloyd; Adam, Catherine; Bray, Thomas L.; Irusta, Silvia; Brennan, Paul M.; Lloyd-Jones, Guy C.; Sieger, Dirk; Santamaria, Jesus; Unciti-Broceta, AsierAngewandte Chemie, International Edition (2017), 56 (41), 12548-12552CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of mols. in complex biol. systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs.
- 109Devaraj, N. K. The future of bioorthogonal chemistry. ACS Cent. Sci. 2018, 4, 952– 959, DOI: 10.1021/acscentsci.8b00251[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGhu7rN&md5=563756ff99c569baa5014a7843d1f0ecThe Future of Bioorthogonal ChemistryDevaraj, Neal K.ACS Central Science (2018), 4 (8), 952-959CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)A review. Bioorthogonal reactions have found widespread use in applications ranging from glycan engineering to in vivo imaging. Researchers have devised numerous reactions that can be predictably performed in a biol. setting. Depending on the requirements of the intended application, one or more reactions from the available toolkit can be readily deployed. As an increasing no. of investigators explore and apply chem. reactions in living systems, it is clear that there are a myriad of ways in which the field may advance. This article presents an outlook on the future of bioorthogonal chem. I discuss currently emerging opportunities and speculate on how bioorthogonal reactions might be applied in research and translational settings. I also outline hurdles that must be cleared if progress toward these goals is to be made. Given the incredible past successes of bioorthogonal chem. and the rapid pace of innovations in the field, the future is undoubtedly very bright.
- 110(a) Zheng, Y.; Ji, X.; Yu, B.; Ji, K.; Gallo, D.; Csizmadia, E.; Zhu, M.; Choudhury, M. R.; De La Cruz, L. K. C.; Chittavong, V.; Pan, Z.; Yuan, Z.; Otterbein, L. E.; Wang, B. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nat. Chem. 2018, 10, 787, DOI: 10.1038/s41557-018-0055-2[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps1KktLk%253D&md5=148c528d5a8c3851abc31145a7b39253Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxideZheng, Yueqin; Ji, Xingyue; Yu, Bingchen; Ji, Kaili; Gallo, David; Csizmadia, Eva; Zhu, Mengyuan; Roy Choudhury, Manjusha; De La Cruz, Ladie Kimberly C.; Chittavong, Vayou; Pan, Zhixiang; Yuan, Zhengnan; Otterbein, Leo E.; Wang, BingheNature Chemistry (2018), 10 (7), 787-794CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Controlled activation is a crit. component in prodrug development. Here we report a concn.-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biol. and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of mols. and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the crit. feasibility of treating clin. relevant diseases such as acute liver injury and cancer.(b) Ji, X.; Pan, Z.; Yu, B.; De La Cruz, L. K.; Zheng, Y.; Ke, B.; Wang, B. Click and release: bioorthogonal approaches to ″on-demand″ activation of prodrugs. Chem. Soc. Rev. 2019, 48, 1077, DOI: 10.1039/C8CS00395E[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisFGjsbs%253D&md5=724cfdbebebc0e5625eb1bf62b04f594Click and release: bioorthogonal approaches to "on-demand" activation of prodrugsJi, Xingyue; Pan, Zhixiang; Yu, Bingchen; De La Cruz, Ladie Kimberly; Zheng, Yueqin; Ke, Bowen; Wang, BingheChemical Society Reviews (2019), 48 (4), 1077-1094CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Prodrug approaches represent an excellent soln. to certain pharmaceutical issues commonly encountered in the drug discovery and development process. Along this line, the chem. needed for the bio-reversible derivatization of drug functional groups for on-demand release is crit. In recent years, "click and release" approaches have shown great promise in the design of prodrugs because of their bioorthogonality and controlled bond-cleavage, which help ensure prodrug stability during circulation and ready cleavage at the desired site of action. This review highlights recent developments of this research field and discusses issues yet to be addressed.
- 111Klán, P.; Šolomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev. 2013, 113, 119– 191, DOI: 10.1021/cr300177k[ACS Full Text], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyiurvL&md5=b8defe84c6c629e44d429f82fa4eb5f0Photoremovable Protecting Groups in Chemistry and Biology: Reaction Mechanisms and EfficacyKlan, Petr; Solomek, Tomas; Bochet, Christian G.; Blanc, Aurelien; Givens, Richard; Rubina, Marina; Popik, Vladimir; Kostikov, Alexey; Wirz, JakobChemical Reviews (Washington, DC, United States) (2013), 113 (1), 119-191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Photoremovable (sometimes called photoreleasable, photocleavable or photoactivatable) protecting groups (PPGs) provide spatial and temporal control over the release of various chems. such as bioagents (neurotransmitters and cell-signaling mols.), acids, bases, Ca2+ ions, oxidants, insecticides, phermones, fragrances, etc. The present review covers recent developments in the field, focusing on the scope, limitations, and applications of PPGs, which are used to release org. mols. Simplified basic structures of PPGs discussed in this review are provided.
- 112Horbert, R.; Pinchuk, B.; Davies, P.; Alessi, D.; Peifer, C. Photoactivatable prodrugs of anti-melanoma agent vemurafenib. ACS Chem. Biol. 2015, 10, 2099– 107, DOI: 10.1021/acschembio.5b00174[ACS Full Text], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVShtb%252FM&md5=5eabb1cd8a1b5d5af1709052f897552fPhotoactivatable Prodrugs of Antimelanoma Agent VemurafenibHorbert, Rebecca; Pinchuk, Boris; Davies, Paul; Alessi, Dario; Peifer, ChristianACS Chemical Biology (2015), 10 (9), 2099-2107CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clin. studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of mols. triggered by UV light. Thus, higher inhibitor concns. in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacol. tools. We investigated their photochem. characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biol. tool for novel pharmacol. approaches in cancer research.
- 113Bliman, D.; Nilsson, J. R.; Kettunen, P.; Andréasson, J.; Grøtli, M. A Caged ret kinase inhibitor and its effect on motoneuron development in zebrafish embryos. Sci. Rep. 2015, 5, 13109, DOI: 10.1038/srep13109[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKht7zN&md5=390c153f289b4be85737a6cfb6e53a57A Caged Ret Kinase Inhibitor and its Effect on Motoneuron Development in Zebrafish EmbryosBliman, David; Nilsson, Jesper R.; Kettunen, Petronella; Andreasson, Joakim; Groetli, MortenScientific Reports (2015), 5 (), 13109CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compds. by attaching photolabile groups to the exocyclic amino function. The most promising compd. displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development.
- 114Zindler, M.; Pinchuk, B.; Renn, C.; Horbert, R.; Döbber, A.; Peifer, C. Design, synthesis, and characterization of a photoactivatable caged prodrug of imatinib. ChemMedChem 2015, 10, 1335– 1338, DOI: 10.1002/cmdc.201500163[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpvFShsbk%253D&md5=2e3389a68aab1816088677fd68cc5981Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of ImatinibZindler, Melanie; Pinchuk, Boris; Renn, Christian; Horbert, Rebecca; Doebber, Alexander; Peifer, ChristianChemMedChem (2015), 10 (8), 1335-1338CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Imatinib is the first protein kinase inhibitor approved for clin. use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by UV light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacol. tool to study the impact of imatinib toward biol. systems in greater detail.
- 115Ieda, N.; Yamada, S.; Kawaguchi, M.; Miyata, N.; Nakagawa, H. (7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity. Bioorg. Med. Chem. 2016, 24, 2789– 2793, DOI: 10.1016/j.bmc.2016.04.042[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFCmt78%253D&md5=1428b487a0fa01f669c3a8b9433a84db(7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activityIeda, Naoya; Yamada, Sota; Kawaguchi, Mitsuyasu; Miyata, Naoki; Nakagawa, HidehikoBioorganic & Medicinal Chemistry (2016), 24 (12), 2789-2793CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Histone deacetylases (HDACs) are involved in epigenetic control of the expression of various genes by catalyzing deacetylation of ε-acetylated lysine residues. Here, we report the design, synthesis and evaluation of the (7-diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid (AC-SAHA) as a caged HDAC inhibitor, which releases the known pan-HDAC inhibitor SAHA upon cleavage of the photolabile (7-diethylaminocoumarin-4-yl)methyl protecting group in response to photoirradn. A key advantage of AC-SAHA is that the caged deriv. itself shows essentially no HDAC-inhibitory activity. Upon photoirradn., AC-SAHA decomps. to SAHA and a 7-diethylaminocoumarin deriv., together with some minor products. We confirmed that AC-SAHA inhibits HDAC in response to photoirradn. in vitro by means of chemiluminescence assay. AC-SAHA also showed photoinduced inhibition of proliferation of human colon cancer cell line HCT116, as detd. by MTT assay. Thus, AC-SAHA should be a useful tool for spatiotemporally controlled inhibition of HDAC activity, as well as a candidate chemotherapeutic reagent for human colon cancer.
- 116Parasar, B.; Chang, P. V. Chemical optogenetic modulation of inflammation and immunity. Chem. Sci. 2017, 8, 1450– 1453, DOI: 10.1039/C6SC03702J[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslalsbfJ&md5=f03308c8d733e0defb03e41032440547Chemical optogenetic modulation of inflammation and immunityParasar, Bibudha; Chang, Pamela V.Chemical Science (2017), 8 (2), 1450-1453CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The immune system is an essential component of host defense against pathogens and is largely mediated by inflammatory mols. produced by immune cells, such as macrophages. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photocontrolled HDAC inhibitors, which can be selectively delivered to target cells by UV irradn. to minimize off-target effects. We strategically photocaged the active moiety of an HDAC inhibitor and showed that mild UV irradn. leads to the selective release of the inhibitor in a spatiotemporal manner. This methodol. was used to decrease the amt. of pro-inflammatory mediators produced by a subpopulation of macrophages. Our approach could ultimately be used to control inflammation in vivo as a therapeutic for inflammatory diseases, while minimizing off-target effects to healthy tissues.
- 117Tamura, R.; Balabanova, A.; Frakes, S. A.; Bargmann, A.; Grimm, J.; Koch, T. H.; Yin, H. H. Photoactivatable prodrug of doxazolidine targeting exosomes. J. Med. Chem. 2019, 62, 1959, DOI: 10.1021/acs.jmedchem.8b01508[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlChuro%253D&md5=777f4de98d7562f37c15faa99fdf19aaPhotoactivatable Prodrug of Doxazolidine Targeting ExosomesTamura, Ryo; Balabanova, Alla; Frakes, Samuel A.; Bargmann, Austin; Grimm, Jan; Koch, Tad H.; Yin, HangJournal of Medicinal Chemistry (2019), 62 (4), 1959-1970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling mols. to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS-ED-photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS-ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS-ED-photodoxaz releases doxaz under near-UV irradn. to inhibit cell growth with low nanomolar IC50 values. The MARCKS-ED-photodoxaz system targeting exosomes and utilizing photochem. will potentially provide a new approach for the treatment of cancer, esp. for highly progressive and invasive metastatic cancers.
- 118Döbber, A.; Phoa, A. F.; Abbassi, R. H.; Stringer, B. W.; Day, B. W.; Johns, T. G.; Abadleh, M.; Peifer, C.; Munoz, L. Development and biological evaluation of a photoactivatable small molecule microtubule-targeting agent. ACS Med. Chem. Lett. 2017, 8, 395– 400, DOI: 10.1021/acsmedchemlett.6b00483[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkt1Ohsrw%253D&md5=d9b653c1d7c8a093f35d840f245ece6dDevelopment and Biological Evaluation of a Photoactivatable Small Molecule Microtubule-Targeting AgentDobber, Alexander; Phoa, Athena F.; Abbassi, Ramzi H.; Stringer, Brett W.; Day, Bryan W.; Johns, Terrance G.; Abadleh, Mohammed; Peifer, Christian; Munoz, LenkaACS Medicinal Chemistry Letters (2017), 8 (4), 395-400CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Abstr.: Photoremovable protecting groups added to bioactive mols. provide spatial and temporal control of the biol. effects. We present synthesis and characterization of the first photoactivatable small-mol. tubulin inhibitor. By blocking the pharmacophoric OH group on compd. 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photo-caged prodrug 2 that had no effect in biol. assays. Short UV light exposure of the deriv. 2 or UV-irradn. of cells treat-ed with 2 resulted in fast and potent inhibition of tubulin polymn., attenuation of cell viability and apoptotic cell death, i.m.-plicating release of the parent active compd. This study validates for the first time the photoactivatable prodrug concept in the field of small mol. tubulin inhibitors. The caged deriv. 2 represents a novel tool in anti-tubulin approaches.
- 119Perdicakis, B.; Montgomery, H. J.; Abbott, G. L.; Fishlock, D.; Lajoie, G. A.; Guillemette, J. G.; Jervis, E. Photocontrol of nitric oxide production in cell culture using a caged isoform selective inhibitor. Bioorg. Med. Chem. 2005, 13, 47– 57, DOI: 10.1016/j.bmc.2004.10.002[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngvVaisg%253D%253D&md5=09a25f1bedf1dceb58123f0aeb690a73Photocontrol of nitric oxide production in cell culture using a caged isoform selective inhibitorPerdicakis Basil; Montgomery Heather J; Abbott Glenn L; Fishlock Dan; Lajoie Gilles A; Guillemette J Guy; Jervis EricBioorganic & medicinal chemistry (2005), 13 (1), 47-57 ISSN:0968-0896.Over the past decade, multiphoton microscopy has progressed from a photonic novelty to a technique whose application is currently experiencing exponential growth in the biological sciences. A novel application of this technology with significant therapeutic potential is the control of drug activity by multiphoton photolysis of caged therapeutics. As an initial case study, the potent isoform selective inhibitor N-(3-(aminomethyl)benzyl) acetamidine (1400W) of inducible nitric oxide synthase (iNOS) has been conjugated to a caging molecule 6-bromo-7-hydroxy-4-hydroxyquinoline-2-ylmethyl acetyl ester (Bhc). Here we present the first report of a bulk therapeutic effect, inhibition of nitric oxide production, in mammalian cell culture by multiphoton photolysis of a caged drug, Bhc-1400W. Mouse macrophage RAW 264.7 cells induced with bacterial lipopolysaccharides to express iNOS were used to assess the therapeutic value of the conjugated inhibitor. Both 1400W and Bhc-1400W are stable in metabolically active cells and an optimal time interval for the photorelease of the inhibitor was determined. The ratios of the IC(50) values of Bhc-1400W over 1400W calculated in the presence of iNOS enzyme and in RAW 264.7 cell culture are 19 and 100, respectively, indicating that a broad therapeutic range exists in cell culture. Multiphoton uncaging protocols and therapeutic doses of inhibitors were not cytotoxic. Photocontrol of LPS induced nitric oxide production was achieved in mammalian cell culture using a single laser focal volume. This technology has the potential to control active drug concentrations in vivo, a lack of which is one of the main problems currently associated with systemic drug administration.
- 120Abrahamse, H.; Hamblin, M. R. New photosensitizers for photodynamic therapy. Biochem. J. 2016, 473, 347– 364, DOI: 10.1042/BJ20150942[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xitleqsrc%253D&md5=9ad9b594476ad2c3452189212f0827b7New photosensitizers for photodynamic therapyAbrahamse, Heidi; Hamblin, Michael R.Biochemical Journal (2016), 473 (4), 347-364CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochem. reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compds. have received clin. approval. Other mol. structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnol. has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochem. internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.
- 121Detty, M. R.; Gibson, S. L.; Wagner, S. J. Current clinical and preclinical photosensitizers for use in photodynamic therapy. J. Med. Chem. 2004, 47, 3897– 3915, DOI: 10.1021/jm040074b[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkvFyht7c%253D&md5=6a04a3f30fc9028e9c49cce437fcc976Current Clinical and Preclinical Photosensitizers for Use in Photodynamic TherapyDetty, Michael R.; Gibson, Scott L.; Wagner, Stephen J.Journal of Medicinal Chemistry (2004), 47 (16), 3897-3915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review, on the current clin. and preclin. photosensitizers use for PDT.
- 122Hirohara, S.; Oka, C.; Totani, M.; Obata, M.; Yuasa, J.; Ito, H.; Tamura, M.; Matsui, H.; Kakiuchi, K.; Kawai, T.; Kawaichi, M.; Tanihara, M. Synthesis, photophysical properties, and biological evaluation of trans-bisthioglycosylated tetrakis(fluorophenyl)chlorin for photodynamic therapy. J. Med. Chem. 2015, 58, 8658– 8670, DOI: 10.1021/acs.jmedchem.5b01262[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Cgu77K&md5=abe9b3cc968e56f3118692e3761d5ca7Synthesis, Photophysical Properties, and Biological Evaluation of trans-bisthioglycosylated Tetrakis(fluorophenyl)chlorin for Photodynamic TherapyHirohara, Shiho; Oka, Chio; Totani, Masayasu; Obata, Makoto; Yuasa, Junpei; Ito, Hiromu; Tamura, Masato; Matsui, Hirofumi; Kakiuchi, Kiyomi; Kawai, Tsuyoshi; Kawaichi, Masashi; Tanihara, MasaoJournal of Medicinal Chemistry (2015), 58 (21), 8658-8670CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Trans-bisthioglycosylated tetrakis(fluorophenyl)chlorin (7) was designed as a powerful photodynamic therapy (PDT) photosensitizer based on the findings of our systematic studies. We show here that the trans-bisthioglycosylated structure of 7 enhanced its uptake by HeLa cells and that the chlorin ring of 7 increased the efficiency of reactive oxygen species generation under the std. condition of our photocytotoxicity test. The versatility of 7 in PDT treatment was established using weakly metastatic B16F1 melanoma cells, metastatic 4T1 breast cancer cells, the RGK-1 gastric carcinoma mucosal cell line, and three human glioblastoma cell lines (U87, U251, and T98G). The pharmacokinetics of 7 in mice bearing 4T1 breast cancer cells showed a high tumor-to-skin concn. ratio (approx. 60) at 24 h after i.p. injection. The PDT efficacy of 7 in vivo was approx. 250-times higher than that of mono-L-aspartyl chlorin e6 (9) in mice bearing 4T1 breast cancer cells.
- 123Monro, S.; Colón, K. L.; Yin, H.; Roque, J., 3rd.; Konda, P.; Gujar, S.; Thummel, R. P.; Lilge, L.; Cameron, C. G.; McFarland, S. A. Transition metal complexes and photodynamic therapy from a tumor-centered approach: challenges, opportunities, and highlights from the development of TLD1433. Chem. Rev. 2019, 119, 797, DOI: 10.1021/acs.chemrev.8b00211[ACS Full Text], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGmtrjK&md5=73b333b327b1f83a6146b321dfe80ba9Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433Monro, Susan; Colon, Katsuya L.; Yin, Huimin; Roque, John; Konda, Prathyusha; Gujar, Shashi; Thummel, Randolph P.; Lilge, Lothar; Cameron, Colin G.; McFarland, Sherri A.Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 797-828CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochem. and photophys. properties derive from a variety of excited-state electronic configurations accessible with visible and near-IR light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiol. activity. Selected examples highlight the use of rational design in coordination chem. to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clin. trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chem. and photophys. solns. that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clin. trial.
- 124Xu, P.; Jia, Y.; Yang, Y.; Chen, J.; Hu, P.; Chen, Z.; Huang, M. Photodynamic oncotherapy mediated by gonadotropin-releasing hormone receptors. J. Med. Chem. 2017, 60, 8667– 8672, DOI: 10.1021/acs.jmedchem.7b01216[ACS Full Text], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyru7vO&md5=e26279d67fc76a1603906ee59a9cc668Photodynamic Oncotherapy Mediated by Gonadotropin-Releasing Hormone ReceptorsXu, Peng; Jia, Yuhua; Yang, Yongshuai; Chen, Jincan; Hu, Ping; Chen, Zhuo; Huang, MingdongJournal of Medicinal Chemistry (2017), 60 (20), 8667-8672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we report photodynamic oncotherapies mediated by gonadotropin-releasing hormone (GnRH) receptors. We synthesized conjugates 1 and 2 by coupling zinc phthalocyanine (ZnPc) to GnRH analogs. Compared to unmodified ZnPc, conjugates 1 and 2 exhibited higher and more specific phototoxicities to breast cancer cells. Furthermore, the two conjugates demonstrated excellent antitumor efficacies in a breast cancer-grafted animal model. Biodistribution study suggested the high biosafety of conjugate 2 because of the low retention in brain and skin.
- 125Thapa, P.; Li, M.; Bio, M.; Rajaputra, P.; Nkepang, G.; Sun, Y.; Woo, S.; You, Y. Far-red light-activatable prodrug of paclitaxel for the combined effects of photodynamic therapy and site-specific paclitaxel chemotherapy. J. Med. Chem. 2016, 59, 3204– 3214, DOI: 10.1021/acs.jmedchem.5b01971[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFejtr4%253D&md5=0e70718577b2b60c93e9f2e3d150b70bFar-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel ChemotherapyThapa, Pritam; Li, Mengjie; Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; Sun, Yajing; Woo, Sukyung; You, YoungjaeJournal of Medicinal Chemistry (2016), 59 (7), 3204-3214CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepd. the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymn. enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clin. useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.
- 126Battah, S.; Hider, R. C.; MacRobert, A. J.; Dobbin, P. S.; Zhou, T. Hydroxypyridinone and 5-aminolaevulinic acid conjugates for photodynamic therapy. J. Med. Chem. 2017, 60, 3498– 3510, DOI: 10.1021/acs.jmedchem.7b00346[ACS Full Text], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsVygtrc%253D&md5=0f83ed82793fce2ed87174a12276347aHydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic TherapyBattah, Sinan; Hider, Robert C.; MacRobert, Alexander J.; Dobbin, Paul S.; Zhou, TaoJournal of Medicinal Chemistry (2017), 60 (8), 3498-3510CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Photodynamic therapy (PDT) is a promising treatment strategy for malignant and non-malignant lesions. 5-Aminolevulinic acid (ALA) is used has a precursor of the photosensitizer, protoporphyrin IX (PpIX) in dermatol. and urol. However, the effectiveness of ALA-PDT is limited by the relatively poor bioavailability of ALA and rapid conversion of PpIX to haem. The main goal of this study was to prep. and investigate a library of single conjugates designed to co-administer the bioactive agents ALA and hydroxypyridinone (HPO) iron chelators. A significant increase in intracellular PpIX levels was obsd. in all cell lines tested when compared to the administration of ALA alone. The higher PpIX levels obsd. using the conjugates correlated well with the obsd. phototoxicity following exposure of cells to light. Passive diffusion appears to be the main mechanism for the majority of ALA-HPOs investigated. This study demonstrates that ALA-HPOs significantly enhance phototherapeutic metabolite formation and phototoxicity.
- 127Feng, X.; Shi, Y.; Xie, L.; Zhang, K.; Wang, X.; Liu, Q.; Wang, P. Synthesis, characterization, and biological evaluation of a porphyrin-based photosensitizer and its isomer for effective photodynamic therapy against breast cancer. J. Med. Chem. 2018, 61, 7189– 7201, DOI: 10.1021/acs.jmedchem.8b00547[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2htbnJ&md5=1cc188053e3eb02466acad3f1b1cffd4Synthesis, Characterization, and Biological Evaluation of a Porphyrin-Based Photosensitizer and Its Isomer for Effective Photodynamic Therapy against Breast CancerFeng, Xiaolan; Shi, Yin; Xie, Lifen; Zhang, Kun; Wang, Xiaobing; Liu, Quanhong; Wang, PanJournal of Medicinal Chemistry (2018), 61 (16), 7189-7201CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A photosensitizer with high phototoxicity, low dark toxicity, and good water soly. is crucial for effective photodynamic therapy (PDT). In this study, a novel class of porphyrin-based water-sol. deriv. and its isomers, named photohexer-1 (P-1) and photohexer-2 (P-2), were synthesized and investigated for anticancer activity. Both of the isomers, P-1 and P-2, could be utilized as potential sensitizers for PDT not only owing to their definite constituents but predominantly due to their good absorption in the phototherapeutic window and high generation of intracellular ROS. Therein, P-2 exhibited stronger phototoxicity against breast cancer cells with weaker dark toxicity than P-1; however, both P-1 and P-2 were highly phototoxic as compared to their homologous compd., hematoporphyrin monomethyl ether (HMME). These findings were consistent with the antitumor efficacy in vivo. Moreover, P-1 and P-2 could both effectively localize in multiple subcellular organelles, triggering increased cellular apoptosis or necrosis under laser irradn. as compared to HMME. In conclusion, the findings of the study suggest that the two highly water-sol. porphyrin derivs. may serve as promising putative photosensitizers for improving the therapeutic efficiency of PDT.
- 128Zhou, Y.; Cheung, Y. K.; Ma, C.; Zhao, S.; Gao, D.; Lo, P. C.; Fong, W. P.; Wong, K. S.; Ng, D. K. P. Endoplasmic reticulum-localized two-photon-absorbing boron dipyrromethenes as advanced photosensitizers for photodynamic therapy. J. Med. Chem. 2018, 61, 3952– 3961, DOI: 10.1021/acs.jmedchem.7b01907[ACS Full Text], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtLs%253D&md5=2eff962be9e0a9c09331d6ab95a7c9d3Endoplasmic Reticulum-Localized Two-Photon-Absorbing Boron Dipyrromethenes as Advanced Photosensitizers for Photodynamic TherapyZhou, Yimin; Cheung, Ying-Kit; Ma, Chao; Zhao, Shirui; Gao, Di; Lo, Pui-Chi; Fong, Wing-Ping; Wong, Kam Sing; Ng, Dennis K. P.Journal of Medicinal Chemistry (2018), 61 (9), 3952-3961CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two advanced boron dipyrromethene (BODIPY) based photosensitizers have been synthesized and characterized. With a glibenclamide analogous moiety, these compds. can localize in the endoplasmic reticulum (ER) of HeLa human cervical carcinoma cells and HepG2 human hepatocarcinoma cells. The BODIPY π skeleton is conjugated with two styryl or carbazolylethenyl groups, which can substantially red-shift the Q-band absorption and fluorescence emission and impart two-photon absorption (TPA) property to the chromophores. The TPA cross section of the carbazole-contg. analog reaches a value of 453 GM at 1010 nm. These compds. also behave as singlet oxygen generators with high photostability. Upon irradn. at λ > 610 nm, these photosensitizers cause photocytotoxicity to these two cell lines with IC50 values down to 0.09 μM, for which the cell death is triggered mainly by ER stress. The two-photon photodynamic activity of the distyryl deriv. upon excitation at λ = 800 nm has also been demonstrated.
- 129Cheruku, R. R.; Cacaccio, J.; Durrani, F.; Tabaczynski, W. A.; Watson, R.; Marko, A. J.; Kumar, R.; El-Khouly, M. E.; Fukuzumi, S.; Missert, J. R.; Yao, R.; Sajjad, M.; Chandra, D.; Guru, K.; Pandey, R. K. Epidermal growth factor receptor targeted multifunctional photosensitizers for bladder cancer imaging and photodynamic therapy. J. Med. Chem. 2019, 62, 2598, DOI: 10.1021/acs.jmedchem.8b01927[ACS Full Text], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFGjsrg%253D&md5=2b6d6c1387d3d847f9a0be8b3f8ee1b1Epidermal Growth Factor Receptor-Targeted Multifunctional Photosensitizers for Bladder Cancer Imaging and Photodynamic TherapyCheruku, Ravindra R.; Cacaccio, Joseph; Durrani, Farukh A.; Tabaczynski, Walter A.; Watson, Ramona; Marko, Aimee; Kumar, Rahul; El-Khouly, Mohamed E.; Fukuzumi, Shunichi; Missert, Joseph R.; Yao, Rutao; Sajjad, Munawwar; Chandra, Dhyan; Guru, Khurshid; Pandey, Ravindra K.Journal of Medicinal Chemistry (2019), 62 (5), 2598-2617CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The in vitro and in vivo anticancer activity of iodinated photosensitizers (PSs) with and without an erlotinib moiety was investigated in UMUC3 [epidermal growth factor (EGFR)-pos.] and T24 (EGFR-low) cell lines and tumored mice. Both the erlotinib-conjugated PSs 3 and 5 showed EGFR target specificity, but the position-3 erlotinib-PS conjugate 3 demonstrated lower photodynamic therapy efficacy than the corresponding non-erlotinib analog 1, whereas the conjugate 5 contg. an erlotinib moiety at position-17 of the PS showed higher tumor uptake and long-term tumor cure (severe combined immunodeficient mice bearing UMUC3 tumors). PS-erlotinib conjugates in the absence of light were ineffective in vitro and in vivo, but robust apoptotic and necrotic cell death was obsd. in bladder cancer cells after exposing them to a laser light at 665 nm. In contrast to 18F-fluorodeoxyglucose, a positron emission tomog. agent, the position-17 erlotinib conjugate (124I-analog 6) showed enhanced UMUC3 tumor contrast even at a low imaging dose of 15 μCi/mouse.
- 130Blacklock, K. M.; Yachnin, B. J.; Woolley, G. A.; Khare, S. D. Computational design of a photocontrolled cytosine deaminase. J. Am. Chem. Soc. 2018, 140, 14– 17, DOI: 10.1021/jacs.7b08709[ACS Full Text], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvF2gsL%252FL&md5=0f8919b263b38a015857fc60b09a2eb8Computational design of a photocontrolled cytosine deaminaseBlacklock, Kristin M.; Yachnin, Brahm J.; Woolley, G. Andrew; Khare, Sagar D.Journal of the American Chemical Society (2018), 140 (1), 14-17CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)There is growing interest in designing spatiotemporal control over enzyme activities using noninvasive stimuli such as light. Here, we describe a structure-based, computation-guided predictive method for reversibly controlling enzyme activity using covalently attached photoresponsive azobenzene groups. Applying the method to the therapeutically useful enzyme yeast cytosine deaminase, we obtained a ∼3-fold change in enzyme activity by the photocontrolled modulation of the enzyme's active site lid structure, while fully maintaining thermostability. Multiple cycles of switching, controllable in real time, are possible. The predictiveness of the method is demonstrated by the construction of a variant that does not photoswitch as expected from computational modeling. Our design approach opens new avenues for optically controlling enzyme function. The designed photocontrolled cytosine deaminases may also aid in improving chemotherapy approaches that utilize this enzyme.
- 131Zhu, M.; Zhou, H. Azobenzene-based small molecular photoswitches for protein modulation. Org. Biomol. Chem. 2018, 16, 8434– 8445, DOI: 10.1039/C8OB02157K[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVaqtbfJ&md5=889c70a0d1443631db1125f9d9364881Azobenzene-based small molecular photoswitches for protein modulationZhu, Mingyan; Zhou, HuchenOrganic & Biomolecular Chemistry (2018), 16 (44), 8434-8445CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Mol. photoswitches are a class of chem. structures that can readily isomerize between distinct geometries upon irradn. with light. Mol. photoswitches are utilized to control protein structure and function with temporal and spatial precision. In this review, we summarize the recent progress in the development of azobenzene-based mol. photoswitches and their applications in the photocontrol of protein structure and function. For clarity of discussion, we divide the known photoswitchable proteins into different categories: protein motifs, ion channels, receptors, and enzymes. Basic approaches and considerations for the structure-guided design of photoswitchable ligands are discussed. The applications and limitations of current photoswitches are also discussed.
- 132(a) Quandt, G.; Höfner, G.; Pabel, J.; Dine, J.; Eder, M.; Wanner, K. T. First photoswitchable neurotransmitter transporter inhibitor: light-induced control of γ-aminobutyric acid transporter 1 (GAT1) activity in mouse brain. J. Med. Chem. 2014, 57, 6809– 6821, DOI: 10.1021/jm5008566[ACS Full Text.], [CAS], Google Scholar132ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCrtL3E&md5=a0887de793bab7d481d46db4c4ea88f7First Photoswitchable Neurotransmitter Transporter Inhibitor: Light-Induced Control of γ-Aminobutyric Acid Transporter 1 (GAT1) Activity in Mouse BrainQuandt, Gabriele; Hoefner, Georg; Pabel, Joerg; Dine, Julien; Eder, Matthias; Wanner, Klaus T.Journal of Medicinal Chemistry (2014), 57 (15), 6809-6821CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be assocd. with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter, which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradn. with light, as demonstrated in GABA uptake assays and electrophysiol. expts. with brain slices, and might be used as a tool compd. for deepening the understanding of mGAT1 function in brain.(b) Lutz, T.; Wein, T.; Höfner, G.; Pabel, J.; Eder, M.; Dine, J.; Wanner, K. T. Development of new photoswitchable azobenzene based γ-aminobutyric acid (GABA) uptake inhibitors with distinctly enhanced potency upon photoactivation. J. Med. Chem. 2018, 61, 6211– 6235, DOI: 10.1021/acs.jmedchem.8b00629[ACS Full Text], [CAS], Google Scholar132bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFyjs7rJ&md5=3266bef7983c46e3dd4e53b3ae2c9f6aDevelopment of New Photoswitchable Azobenzene Based γ-Aminobutyric Acid (GABA) Uptake Inhibitors with Distinctly Enhanced Potency upon PhotoactivationLutz, Toni; Wein, Thomas; Hoefner, Georg; Pabel, Joerg; Eder, Matthias; Dine, Julien; Wanner, Klaus T.Journal of Medicinal Chemistry (2018), 61 (14), 6211-6235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of nipecotic acid derivs. with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at γ-aminobutyric acid transporters subtype 1 (GAT1), the most common γ-aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradn. For the most efficient photoactivatable nipecotic acid deriv. displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its (E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
- 133Nørager, N. G.; Poulsen, M. H.; Strømgaard, K. Controlling Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors with photochromic ion channel blockers. J. Med. Chem. 2018, 61, 8048– 8053, DOI: 10.1021/acs.jmedchem.8b00756[ACS Full Text], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7pvVemtg%253D%253D&md5=d18ecb8d74f1f1dc69a713a8fc4f44abControlling Ca(2+) Permeable α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Photochromic Ion Channel BlockersNorager Niels G; Poulsen Mette H; Stromgaard KristianJournal of medicinal chemistry (2018), 61 (17), 8048-8053 ISSN:.Ionotropic glutamate receptors (iGluRs) play a critical role in normal brain function and neurodegenerative diseases. Development of light-dependent compounds would enable studies of iGluRs within intact mammalian neural tissue, as light is noninvasive and can be applied with high spatiotemporal precision. Here we develop a potent photochromic antagonist that selectively targets the Ca(2+) permeable AMPA-type of iGuRs, thus providing an important tool to study the contribution of AMPA-type iGluRs on neuronal activity.
- 134Matera, C.; Gomila, A. M. J.; Camarero, N.; Libergoli, M.; Soler, C.; Gorostiza, P. Photoswitchable antimetabolite for targeted photoactivated chemotherapy. J. Am. Chem. Soc. 2018, 140, 15764– 15773, DOI: 10.1021/jacs.8b08249[ACS Full Text], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2rs77L&md5=72c17ae2b4c36e10e72f9485bc851091Photoswitchable Antimetabolite for Targeted Photoactivated ChemotherapyMatera, Carlo; Gomila, Alexandre M. J.; Camarero, Nuria; Libergoli, Michela; Soler, Concepcio; Gorostiza, PauJournal of the American Chemical Society (2018), 140 (46), 15764-15773CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small mols. and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.
- 135Li, J.; Kong, H.; Huang, L.; Cheng, B.; Qin, K.; Zheng, M.; Yan, Z.; Zhang, Y. Visible light-initiated bioorthogonal photoclick cycloaddition. J. Am. Chem. Soc. 2018, 140, 14542– 14546, DOI: 10.1021/jacs.8b08175[ACS Full Text], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvF2mt7%252FI&md5=40821844ee74b4194ea983b7cbf4ff89Visible Light-Initiated Bioorthogonal Photoclick CycloadditionLi, Jinbo; Kong, Hao; Huang, Lei; Cheng, Bo; Qin, Ke; Zheng, Mengmeng; Yan, Zheng; Zhang, YanJournal of the American Chemical Society (2018), 140 (44), 14542-14546CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Here we report a visible light-triggered, catalyst free bioorthogonal reaction that proceeds via a distinct pathway from reported bioorthogonal reactions. The prototype of this bioorthogonal reaction was the photocycloaddn. of 9,10-phenanthrenequinone with electron-rich alkenes to form fluorogenic [4+2] cycloadducts. The bioorthogonal photoclick cycloaddn. was readily initiated using a conventional visible light source such as a hand-held LED lamp. The reaction proceeded rapidly under biocompatible conditions, without observable competition from side reactions such as nucleophilic addns. by water or common nucleophilic species. The bioorthogonal functionality in this reaction did not cross react with various alkynes and electron-deficient alkenes such as monomethyl fumarate. We demonstrated orthogonal labeling of two proteins using this reaction together with a strain promoting azide-alkyne click reaction or the UV-triggered reaction of tetrazole with monomethyl fumarate. The application of this reaction in the temporal and spatial labeling of live cells was also demonstrated.
- 136Comer, E.; Beaudoin, J. A.; Kato, N.; Fitzgerald, M. E.; Heidebrecht, R. W.; Lee, Md, 4th.; Masi, D.; Mercier, M.; Mulrooney, C.; Muncipinto, G.; Rowley, A.; Crespo-Llado, K.; Serrano, A. E.; Lukens, A. K.; Wiegand, R. C.; Wirth, D. F.; Palmer, M. A.; Foley, M. A.; Munoz, B.; Scherer, C. A.; Duvall, J. R.; Schreiber, S. L. Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents. J. Med. Chem. 2014, 57, 8496– 8502, DOI: 10.1021/jm500994n[ACS Full Text], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFams77O&md5=05ec57a8972d21220ccae6e57fb37664Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial AgentsComer, Eamon; Beaudoin, Jennifer A.; Kato, Nobutaka; Fitzgerald, Mark E.; Heidebrecht, Richard W.; Lee, Maurice duPont; Masi, Daniela; Mercier, Marion; Mulrooney, Carol; Muncipinto, Giovanni; Rowley, Ann; Crespo-Llado, Keila; Serrano, Adelfa E.; Lukens, Amanda K.; Wiegand, Roger C.; Wirth, Dyann F.; Palmer, Michelle A.; Foley, Michael A.; Munoz, Benito; Scherer, Christina A.; Duvall, Jeremy R.; Schreiber, Stuart L.Journal of Medicinal Chemistry (2014), 57 (20), 8496-8502CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we describe medicinal chem. that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved soly. and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the prepn. of the original screening library, facilitated medicinal chem. optimization of the antimalarial lead.
- 137Kuttruff, C. A.; Haile, M.; Kraml, J.; Tautermann, C. S. Late-stage functionalization of drug-like molecules using diversinates. ChemMedChem 2018, 13, 983– 987, DOI: 10.1002/cmdc.201800151[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotFWisbY%253D&md5=92d3e35516843c572aff18331897e0feLate-Stage Functionalization of Drug-Like Molecules Using DiversinatesKuttruff, Christian A.; Haile, Margit; Kraml, Johannes; Tautermann, Christofer S.ChemMedChem (2018), 13 (10), 983-987CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Late-stage functionalization (LSF) is a powerful method to quickly generate new analogs of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late-stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, decrease reaction time, and increase reaction yields, we have developed new functionalization conditions involving iron(III) catalysis. Finally, we demonstrate how our LSF reactions using Baran Diversinates can lead to new analogs with improved in vitro DMPK parameters.
- 138Caro-Diaz, E. J. E.; Urbano, M.; Buzard, D. J.; Jones, R. M. C-H activation reactions as useful tools for medicinal chemists. Bioorg. Med. Chem. Lett. 2016, 26, 5378– 5383, DOI: 10.1016/j.bmcl.2016.06.036[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSlsLfF&md5=ac6533ee047115f06062d46be1247881C-H activation reactions as useful tools for medicinal chemistsCaro-Diaz, Eduardo J. E.; Urbano, Mariangela; Buzard, Daniel J.; Jones, Robert M.Bioorganic & Medicinal Chemistry Letters (2016), 26 (22), 5378-5383CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. In recent years, there has been an exponential rise in the no. of reports describing synthetic methods that utilize catalytic sp3 and sp2 C-H bond activation. Many have emerged as powerful synthetic tools for accessing biol. active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chem.
- 139Sekizawa, H.; Amaike, K.; Itoh, Y.; Suzuki, T.; Itami, K.; Yamaguchi, J. Late-stage C-H coupling enables rapid identification of HDAC inhibitors: synthesis and evaluation of NCH-31 analogues. ACS Med. Chem. Lett. 2014, 5, 582– 586, DOI: 10.1021/ml500024s[ACS Full Text], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjsVehs70%253D&md5=57848d9256b3be492fb405393567ea5fLate-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 AnaloguesSekizawa, Hiromi; Amaike, Kazuma; Itoh, Yukihiro; Suzuki, Takayoshi; Itami, Kenichiro; Yamaguchi, JunichiroACS Medicinal Chemistry Letters (2014), 5 (5), 582-586CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogs of NCH-31 with different aryl groups at the C4-position of the 2-aminothiazole core of NCH-31. Subsequent biol. testing of these derivs. revealed that 3-fluorophenyl (I) and 4-fluorophenyl (II) derivs. act as potent pan-HDAC inhibitor. Addnl., 4-methylphenyl and 3-fluoro-4-methylphenyl derivs. acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional mols.
- 140Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K. Stereodivergent synthesis of arylcyclopropylamines by sequential C-H borylation and Suzuki-Miyaura coupling. Angew. Chem., Int. Ed. 2015, 54, 846– 851, DOI: 10.1002/anie.201409186[Crossref], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVKrsA%253D%253D&md5=6e08f4a20cdcc7481b0cc1444a86f517Stereodivergent Synthesis of Arylcyclopropylamines by Sequential C-H Borylation and Suzuki-Miyaura CouplingMiyamura, Shin; Araki, Misaho; Suzuki, Takayoshi; Yamaguchi, Junichiro; Itami, KenichiroAngewandte Chemie, International Edition (2015), 54 (3), 846-851CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C(sp3)-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is obsd. under the reaction conditions. This epimerization is, however, suppressed in the presence of O2. The present new ACPA synthesis results in not only a significant redn. in the steps required for making ACPA derivs., but also the ability to access either isomer (cis or trans) by simply changing the atm. (N2 or O2) in the coupling stage.
- 141El Marrouni, A.; Campbell, M.; Perkins, J. J.; Converso, A. Development of a sp(2)-sp(3) stille cross-coupling for rapid synthesis of HIV NNRTI doravirine analogues. Org. Lett. 2017, 19, 3071– 3074, DOI: 10.1021/acs.orglett.7b01142[ACS Full Text], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kgtbc%253D&md5=4529cbaf18461b6bf22b1c80b28beba0Development of a sp2-sp3 Stille Cross-Coupling for Rapid Synthesis of HIV NNRTI Doravirine AnaloguesEl Marrouni, Abdellatif; Campbell, Mark; Perkins, James J.; Converso, AntonellaOrganic Letters (2017), 19 (12), 3071-3074CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The development of a C(sp2)-C(sp3) cross-coupling reaction for rapid, parallel synthesis of analogs of two HIV NNRTI clin. candidates is described. This method allowed easy access to the C-ring space using a practical alkylation with com. available tributyl(iodomethyl)stannane followed by a palladium-catalyzed coupling with a variety of aryl halides (I, Br) in the presence of copper chloride. Optimization and scope of this method are reported.
- 142Naret, T.; Khelifi, I.; Provot, O.; Bignon, J.; Levaique, H.; Dubois, J.; Souce, M.; Kasselouri, A.; Deroussent, A.; Paci, A.; Varela, P. F.; Gigant, B.; Alami, M.; Hamze, A. 1,1-Diheterocyclic ethylenes derived from quinaldine and carbazole as new tubulin polymerization inhibitors: synthesis, metabolism, and biological evaluation. J. Med. Chem. 2019, 62, 1902, DOI: 10.1021/acs.jmedchem.8b01386[ACS Full Text], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKrsbfK&md5=d03170fb8982119e7e0c51934a8500c91,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological EvaluationNaret, Timothee; Khelifi, Ilhem; Provot, Olivier; Bignon, Jerome; Levaique, Helene; Dubois, Joelle; Souce, Martin; Kasselouri, Athena; Deroussent, Alain; Paci, Angelo; Varela, Paloma F.; Gigant, Benoit; Alami, Mouad; Hamze, AbdallahJournal of Medicinal Chemistry (2019), 62 (4), 1902-1916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,1-Diheteroaryl ethylenes such as I were prepd. as isocombretastatin-A4 analogs and tested for their antitumor activities and inhibition of tubulin polymn. Palladium-catalyzed coupling of the tosylhydrazones of heteroaryl Me ketones with heteroaryl halides yielded 1,1-diheteroaryl ethylenes. The antitumor activities in a panel of human cancer cell lines, the effects on angiogenesis and cell cycle advancement, metab. in rat and human liver microsomes, and calcd. physicochem. properties for selected compds. were detd. For example, I inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range and showed activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. The structure of I bound to tubulin was detd. by X-ray crystallog. I may be a possible candidate for the treatment of glioblastoma.
- 143Brown, D. G.; Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone?. J. Med. Chem. 2016, 59, 4443– 4458, DOI: 10.1021/acs.jmedchem.5b01409[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVeqsrzM&md5=fd56ba8418f6d4e8c271f4e977ee2a93Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?Brown, Dean G.; Bostrom, JonasJournal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
- 144Fier, P. S.; Maloney, K. M. NHC-Catalyzed deamination of primary sulfonamides: a platform for late-stage functionalization. J. Am. Chem. Soc. 2019, 141, 1441, DOI: 10.1021/jacs.8b11800[ACS Full Text], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVajtbs%253D&md5=3f8d1a52927370182dd701241cce18c3NHC-Catalyzed Deamination of Primary Sulfonamides: A Platform for Late-Stage FunctionalizationFier, Patrick S.; Maloney, Kevin M.Journal of the American Chemical Society (2019), 141 (4), 1441-1445CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary alkyl and aryl sulfonamides underwent chemoselective deamination reactions with benzaldehyde and K2CO3 in the presence of a pyrrolotriazolium chloride via N-benzylidenesulfonamides to yield sulfinate salts; the sulfinates were converted in situ to Me and aryl sulfones, sulfonic acids, and sulfonamides. Reaction of the sulfinates with MeI in DMF yielded Me sulfones, while oxidn. with H2O2 in the presence of tungstic acid yielded sulfonic acids. Reaction of the sulfinate generated from celecoxib with 15NH4OH yielded the corresponding 15N-labeled sulfonamide; coupling reactions of the celecoxib-derived sulfinate with iodobenzene and a chloropyridine yielded aryl sulfones, while desulfonative coupling with Ph triflate yielded a biphenylpyrazole. The method tolerated nearly all common functional groups, including primary amines, and was used for the late-stage derivatization of several complex pharmaceutical compds.
- 145Uehling, M. R.; King, R. P.; Krska, S. W.; Cernak, T.; Buchwald, S. L. Pharmaceutical diversification via palladium oxidative addition complexes. Science 2019, 363, 405– 408, DOI: 10.1126/science.aac6153[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1anu7s%253D&md5=1e241f2157cd0f6dda80fe8c637b90cePharmaceutical diversification via palladium oxidative addition complexesUehling, Mycah R.; King, Ryan P.; Krska, Shane W.; Cernak, Tim; Buchwald, Stephen L.Science (Washington, DC, United States) (2019), 363 (6425), 405-408CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Palladium-catalyzed cross-coupling reactions have transformed the exploration of chem. space in the search for materials, medicines, chem. probes, and other functional mols. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addn. complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of bench-top storage under ambient conditions. We demonstrated the utility of OACs in a variety of expts. including automated nanomole-scale couplings between an OAC derived from rivaroxaban (I) and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.
- 146Clark, J. R.; Feng, K.; Sookezian, A.; White, M. C. Manganese-catalysed benzylic C(sp(3))-H amination for late-stage functionalization. Nat. Chem. 2018, 10, 583– 591, DOI: 10.1038/s41557-018-0020-0[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVCkur4%253D&md5=37c6b2d770fabbd4b6ec6bf31d4877c6Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalizationClark, Joseph R.; Feng, Kaibo; Sookezian, Anasheh; White, M. ChristinaNature Chemistry (2018), 10 (6), 583-591CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Reactions that directly install nitrogen into C-H bonds of complex mols. are significant because of their potential to change the chem. and biol. properties of a given compd. Although selective intramol. C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermol. C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermol. benzylic C-H amination of bioactive mols. and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Bronsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-detg. step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalyzed C-H aminations and provide new opportunities for tunable selectivities.
- 147Margrey, K. A.; Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E. J. A general strategy for aliphatic C-H functionalization enabled by organic photoredox catalysis. J. Am. Chem. Soc. 2018, 140, 4213– 4217, DOI: 10.1021/jacs.8b00592[ACS Full Text], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktlCqt7s%253D&md5=ec9e4b9d881aa159e6cfbd02fca643beA General Strategy for Aliphatic C-H Functionalization Enabled by Organic Photoredox CatalysisMargrey, Kaila A.; Czaplyski, William L.; Nicewicz, David A.; Alexanian, Erik J.Journal of the American Chemical Society (2018), 140 (12), 4213-4217CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Synthetic transformations that functionalize unactivated aliph. C-H bonds in an intermol. fashion offer unique strategies for the synthesis and late-stage derivatization of complex mols. Herein we report a general approach to the intermol. functionalization of aliph. C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradn. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes.
- 148Laudadio, G.; Govaerts, S.; Wang, Y.; Ravelli, D.; Koolman, H. F.; Fagnoni, M.; Djuric, S. W.; Noël, T. Selective C(sp3)-H aerobic oxidation enabled by decatungstate photocatalysis in flow. Angew. Chem., Int. Ed. 2018, 57, 4078– 4082, DOI: 10.1002/anie.201800818[Crossref], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1Gqu7g%253D&md5=7624e1eb218601fb8c9b94c65b9dfa1fSelective C(sp3)-H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in FlowLaudadio, Gabriele; Govaerts, Sebastian; Wang, Ying; Ravelli, Davide; Koolman, Hannes F.; Fagnoni, Maurizio; Djuric, Stevan W.; Noel, TimothyAngewandte Chemie, International Edition (2018), 57 (15), 4078-4082CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A mild and selective C(sp3)-H aerobic oxidn. enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradn. of the reaction mixt. Our method allows for the oxidn. of both activated and unactivated C-H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (-)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, exemplifies the utility of this new method.
- 149Liu, Z.; Li, J.; Li, S.; Li, G.; Sharpless, K. B.; Wu, P. SuFEx click chemistry enabled late-stage drug functionalization. J. Am. Chem. Soc. 2018, 140, 2919– 2925, DOI: 10.1021/jacs.7b12788[ACS Full Text], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVSlu7w%253D&md5=f42bd4b58df0ae8f3ca5a03feb156b0aSuFEx Click Chemistry Enabled Late-Stage Drug FunctionalizationLiu, Zilei; Li, Jie; Li, Suhua; Li, Gencheng; Sharpless, K. Barry; Wu, PengJournal of the American Chemical Society (2018), 140 (8), 2919-2925CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chem. transformations which relies on readily available materials to produce compds. bearing the SVI-F motif. The potential of SuFEx in drug discovery has just started to be explored. The authors report the first method of SuFEx chem. for the conversion of phenolic compds. to their resp. arylfluorosulfate derivs. in situ in 96-well plates. This method is compatible with automated synthesis and screening to quickly assess the biol. activities of the in situ generated, crude products. Using this method, the authors perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates. These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors. The authors discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors. Among these three compds., the fluorosulfate deriv. of Fulvestrant possesses significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7 and the fluorosulfate deriv. of Combretastatin A4-a general anticancer drug currently being evaluated under clin. trials-exhibits a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29.
- 150Boström, J.; Brown, D. G.; Young, R. J.; Keserü, G. M. Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discovery 2018, 17, 709, DOI: 10.1038/nrd.2018.116[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3htlWisw%253D%253D&md5=d87e988602808139597576ced56faa88Expanding the medicinal chemistry synthetic toolboxBostrom Jonas; Brown Dean G; Young Robert J; Keseru Gyorgy MNature reviews. Drug discovery (2018), 17 (10), 709-727 ISSN:.The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.
- 151Roughley, S. D.; Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 2011, 54, 3451– 3479, DOI: 10.1021/jm200187y[ACS Full Text], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsrg%253D&md5=a94df26d82bbd58b269ed20aa3253f56The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug CandidatesRoughley, Stephen D.; Jordan, Allan M.Journal of Medicinal Chemistry (2011), 54 (10), 3451-3479CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. A survey of selected medicinal chem. literature from 2008 was undertaken in order to det. the most common chem. reactions used in the prepn. of drug candidates. In addn. to an examn. of the reactions, the frequency of occurrence of various functional groups in the drug targets was analyzed. The Lipinski parameters and chirality of the surveyed compds. were also discussed.
- 152Frédérich, M.; Pirotte, B.; Fillet, M.; de Tullio, P. Metabolomics as a challenging approach for medicinal chemistry and personalized medicine. J. Med. Chem. 2016, 59, 8649– 8666, DOI: 10.1021/acs.jmedchem.5b01335[ACS Full Text], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2lsr4%253D&md5=b7a0f8f2559582d7489ec0270663f9c3Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized MedicineFrederich, Michel; Pirotte, Bernard; Fillet, Marianne; de Tullio, PascalJournal of Medicinal Chemistry (2016), 59 (19), 8649-8666CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)"Omics" sciences have been developed to provide a holistic point of view of biol. and to better understand the complexity of an organism as a whole. These systems biol. approaches can be examd. at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qual. and quant. study of metabolites. This emerging field is clearly linked to genomics, transcriptomics, and proteomics. In addn., metabolomics provides a unique and direct vision of the functional outcome of an organism's activities that are required for it to survive, grow, and respond to internal and external stimuli or stress, e.g., pathologies and drugs. The links between metabolic changes, patient phenotype, physiol. and/or pathol. status, and treatment are now well established and have opened a new area for the application of metabolomics in the drug discovery process and in personalized medicine.
- 153(a) Stepan, A. F.; Tran, T. P.; Helal, C. J.; Brown, M. S.; Chang, C.; O’Connor, R. E.; De Vivo, M.; Doran, S. D.; Fisher, E. L.; Jenkinson, S.; Karanian, D.; Kormos, B. L.; Sharma, R.; Walker, G. S.; Wright, A. S.; Yang, E. X.; Brodney, M. A.; Wager, T. T.; Verhoest, P. R.; Obach, R. S. Late-stage microsomal oxidation reduces drug-drug interaction and identifies phosphodiesterase 2A inhibitor PF-06815189. ACS Med. Chem. Lett. 2018, 9, 68– 72, DOI: 10.1021/acsmedchemlett.7b00343[ACS Full Text.], [CAS], Google Scholar153ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Wqsg%253D%253D&md5=86a976a3eebf2bbbb9865ae655909ab7Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189Stepan, Antonia F.; Tran, Tuan P.; Helal, Christopher J.; Brown, Maria S.; Chang, Cheng; O'Connor, Rebecca E.; De Vivo, Michael; Doran, Shawn D.; Fisher, Ethan L.; Jenkinson, Stephen; Karanian, David; Kormos, Bethany L.; Sharma, Raman; Walker, Gregory S.; Wright, Ann S.; Yang, Edward X.; Brodney, Michael A.; Wager, Travis T.; Verhoest, Patrick R.; Obach, R. ScottACS Medicinal Chemistry Letters (2018), 9 (2), 68-72CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Late-stage oxidn. using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P 450 enzymes, introduce renal clearance and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 with improved physicochem. properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.(b) Obach, R. S.; Walker, G. S.; Sharma, R.; Jenkinson, S.; Tran, T. P.; Stepan, A. F. Lead diversification at the nanomole scale using liver microsomes and quantitative nuclear magnetic resonance spectroscopy: application to phosphodiesterase 2 inhibitors. J. Med. Chem. 2018, 61, 3626– 3640, DOI: 10.1021/acs.jmedchem.8b00116[ACS Full Text], [CAS], Google Scholar153bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXms1artbs%253D&md5=10c4e199e4c58bd90661851fdc3bc1a6Lead Diversification at the Nanomole Scale Using Liver Microsomes and Quantitative Nuclear Magnetic Resonance Spectroscopy: Application to Phosphodiesterase 2 InhibitorsObach, R. Scott; Walker, Gregory S.; Sharma, Raman; Jenkinson, Stephen; Tran, Tuan P.; Stepan, Antonia F.Journal of Medicinal Chemistry (2018), 61 (8), 3626-3640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In this report, we describe a method whereby lead mols. can be converted into several new analogs each using liver microsomes. Less than one micromole of substrate is incubated with liver microsomes (mouse, rat, hamster, guinea pig, rabbit, dog, monkey, or human) to produce multiple products which are isolated and analyzed by quant. cryomicroprobe NMR (qNMR) spectroscopy. The solns. from qNMR anal. were then used as stocks that were dild. into biochem. assays. Nine human phosphodiesterase-2 (PDE2) inhibitors yielded 36 new analogs. Products were tested for PDE2 inhibition, intrinsic clearance in human hepatocytes, and membrane permeability. Two of the products (2c and 4b) were 3-10× more potent than their resp. parent compds. and also had improved metabolic stability. Others offered insights into structure-activity relationships. Overall, this process of using liver microsomes at a submicromole scale of substrate is a useful approach to rapid and cost-effective late-stage lead diversification.
- 154Clouthier, C. M.; Pelletier, J. N. Expanding the organic toolbox: a guide to integrating biocatalysis in synthesis. Chem. Soc. Rev. 2012, 41, 1585– 1605, DOI: 10.1039/c2cs15286j[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVajs78%253D&md5=a4ccf3d71518dd5dba80c21dc08c7ad4Expanding the organic toolbox. A guide to integrating biocatalysis in synthesisClouthier, Christopher M.; Pelletier, Joelle N.Chemical Society Reviews (2012), 41 (4), 1585-1605CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review presented an introduction to biocatalysis for synthetic chemists. Advances in biocatalysis of the past 5 years illustrate the breadth of applications for these powerful and selective catalysts in conducting key reaction steps. Asym. synthesis of value-added targets and other reaction types were covered, with an emphasis on pharmaceutical intermediates and bulk chems. Resources of interest for the non-initiated are provided, including specialized web-sites and service providers to facilitate identification of suitable biocatalysts, as well as refs. to recent vols. and reviews for more detailed biocatalytic procedures. Challenges related to the application of biocatalysts were discussed, including how green a biocatalytic reaction may be, and trends in biocatalyst improvement through enzyme engineering were presented (152 refs.).
- 155Segall, M. Advances in multiparameter optimization methods for de novo drug design. Expert Opin. Drug Discovery 2014, 9, 803– 817, DOI: 10.1517/17460441.2014.913565[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cnovFyltA%253D%253D&md5=a5cacbf56c2b849325259b8af9b6523bAdvances in multiparameter optimization methods for de novo drug designSegall MatthewExpert opinion on drug discovery (2014), 9 (7), 803-17 ISSN:.INTRODUCTION: A high-quality drug must achieve a balance of physicochemical and absorption, distribution, metabolism and elimination properties, safety and potency against its therapeutic target(s). Multiparameter optimization (MPO) methods guide the simultaneous optimization of multiple factors to quickly target compounds with the highest chance of downstream success. MPO can be combined with 'de novo design' methods to automatically generate and assess a large number of diverse structures and identify strategies to optimize a compound's overall balance of properties. AREAS COVERED: The article provides a review of MPO methods and recent developments in the methods and opinions in the field. It also provides a description of advances in de novo design that improve the relevance of automatically generated compound structures and integrate MPO. Finally, the article provides discussion of a recent case study of the automatic design of ligands to polypharmacological profiles. EXPERT OPINION: Recent developments have reduced the generation of chemically infeasible structures and improved the quality of compounds generated by de novo design methods. There are concerns about the ability of simple drug-like properties and ligand efficiency indices to effectively guide the detailed optimization of compounds. De novo design methods cannot identify a perfect compound for synthesis, but it can identify high-quality ideas for detailed consideration by an expert scientist.
- 156Segall, M. D.; Yusof, I.; Champness, E. J. Avoiding missed opportunities by analyzing the sensitivity of our decisions. J. Med. Chem. 2016, 59, 4267– 4277, DOI: 10.1021/acs.jmedchem.5b01921[ACS Full Text], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmu7c%253D&md5=ee3d2630efd9eb85c1a576a9dc70bbffAvoiding Missed Opportunities by Analyzing the Sensitivity of Our DecisionsSegall, Matthew D.; Yusof, Iskander; Champness, Edmund J.Journal of Medicinal Chemistry (2016), 59 (9), 4267-4277CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Drug discovery is a multiparameter optimization process in which the goal of a project is to identify compds. that meet multiple property criteria required to achieve a therapeutic objective. However, once a profile of property criteria has been chosen, the impact of these criteria on the decisions made regarding progression of compds. or chem. series should be carefully considered. In some cases the decision is very sensitive to a specific property criterion, and such a criterion may artificially distort the direction of the project; any uncertainty in the "correct" value or the importance of this criterion may lead to valuable opportunities being missed. In this paper, we describe a method for analyzing the sensitivity of the prioritization of compds. to a multiparameter profile of property criteria. We show how the results can be easily interpreted and illustrate how this anal. can highlight new avenues for exploration.
- 157Shultz, M. D. Two decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 2019, 62, 1701, DOI: 10.1021/acs.jmedchem.8b00686[ACS Full Text], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslait73K&md5=d3c8b1107133dc0b7b277d22fa029597Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral DrugsShultz, Michael D.Journal of Medicinal Chemistry (2019), 62 (4), 1701-1714CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize mols. based on Ro5 parameters evolved into the introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examn. of oral drug parameters approved before and after the original Ro5 anal. demonstrates that some parameters such as clogP and HBD remained const. while the cutoffs for parameters such as mol. wt. and HBA have increased substantially over the past 20 years. The time dependent increase in the mol. wt. of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that mol. wt. is a "drug-like" property. This anal. does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist.
- 158Doak, B. C.; Zheng, J.; Dobritzsch, D.; Kihlberg, J. How beyond rule of 5 drugs and clinical candidates bind to their targets. J. Med. Chem. 2016, 59, 2312– 2327, DOI: 10.1021/acs.jmedchem.5b01286[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Cgu77F&md5=a417b605d1a3ffbc7ee84706401f01f4How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their TargetsDoak, Bradley C.; Zheng, Jie; Dobritzsch, Doreen; Kihlberg, JanJournal of Medicinal Chemistry (2016), 59 (6), 2312-2327CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To improve discovery of drugs for difficult targets, the opportunities of chem. space beyond the rule of 5 (bRo5) were examd. by retrospective anal. of a comprehensive set of structures for complexes between drugs and clin. candidates and their targets. The anal. illustrates the potential of compds. far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
- 159DeGoey, D. A.; Chen, H. J.; Cox, P. B.; Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 2018, 61, 2636– 2651, DOI: 10.1021/acs.jmedchem.7b00717[ACS Full Text], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeitbjJ&md5=48984dc65410d83d4ac8ddaca030b024Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound CollectionDeGoey, David A.; Chen, Hui-Ju; Cox, Philip B.; Wendt, Michael D.Journal of Medicinal Chemistry (2018), 61 (7), 2636-2651CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncol. and virol. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chem. space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective anal. of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compds. and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclin. PK results with cLogD, no. of rotatable bonds, and no. of arom. rings.
- 160Raymer, B.; Bhattacharya, S. K. Lead-like drugs: A perspective. J. Med. Chem. 2018, 61, 10375, DOI: 10.1021/acs.jmedchem.8b00407[ACS Full Text], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2is73O&md5=e9fc17d69c7d671459fdaf77d6721829Lead-like Drugs: A PerspectiveRaymer, Brian; Bhattacharya, Samit K.Journal of Medicinal Chemistry (2018), 61 (23), 10375-10384CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lead-like drugs, or drugs below mol. wt. 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chem. practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chem. optimization being the choice of a low mol. wt. starting point and maintaining low mol. wt. during the optimization. However, the identification of low mol. wt. starting points may be limited by the availability of suitable low mol. wt. screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.
- 161Johnson, T. W.; Gallego, R. A. Lipophilic efficiency as an important metric in drug design. J. Med. Chem. 2018, 61, 6401– 6420, DOI: 10.1021/acs.jmedchem.8b00077[ACS Full Text], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsVahsbg%253D&md5=29f38880914fa75c33be3a640ace4309Lipophilic Efficiency as an Important Metric in Drug DesignJohnson, Ted W.; Gallego, Rebecca A.; Edwards, Martin P.Journal of Medicinal Chemistry (2018), 61 (15), 6401-6420CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Lipophilic efficiency (LipE) is an important metric that has been increasingly applied in drug discovery medicinal chem. lead optimization programs. In this perspective, using literature drug discovery examples, we discuss the concept of rigorously applying LipE to guide medicinal chem. lead optimization toward drug candidates with potential for superior in vivo efficacy and safety, esp. when guided by physiochem. property-based optimization (PPBO). Also highlighted are examples of small structural modifications such as addn. of single atoms, small functional groups, and cyclizations that produce large increases in LipE. Understanding the factors that may contribute to LipE changes through anal. of ligand-protein crystal structures and using structure-based drug design (SBDD) to increase LipE by design is also discussed. Herein we advocate for use of LipE anal. coupled with PPBO and SBDD as an efficient mechanism for drug design.
- 162Wager, T. T.; Kormos, B. L.; Brady, J. T.; Will, Y.; Aleo, M. D.; Stedman, D. B.; Kuhn, M.; Chandrasekaran, R. Y. Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J. Med. Chem. 2013, 56, 9771– 9779, DOI: 10.1021/jm401485p[ACS Full Text], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslOms7%252FL&md5=7efd1be4dbede3e4d3201154929bd641Improving the Odds of Success in Drug Discovery: Choosing the Best Compounds for in Vivo Toxicology StudiesWager, Travis T.; Kormos, Bethany L.; Brady, Joseph T.; Will, Yvonne; Aleo, Michael D.; Stedman, Donald B.; Kuhn, Max; Chandrasekaran, Ramalakshmi Y.Journal of Medicinal Chemistry (2013), 56 (23), 9771-9779CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A set of mols. that advanced into exploratory animal toxicol. studies (two species) was examd. to det. what properties contributed to success in these safety studies. Compds. were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicol. studies. The most predictive end point contributing to compd. survival was a predicted human efficacious concn. (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters.
- 163(a) Shultz, M. D.; Majumdar, D.; Chin, D. N.; Fortin, P. D.; Feng, Y.; Gould, T.; Kirby, C. A.; Stams, T.; Waters, N. J.; Shao, W. Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases. J. Med. Chem. 2013, 56, 7049– 7059, DOI: 10.1021/jm400826j[ACS Full Text.], [CAS], Google Scholar163ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCmu7%252FL&md5=b9174e9070c813b598cf15b261de9471Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrasesShultz, Michael D.; Majumdar, Dyuti; Chin, Donovan N.; Fortin, Pascal D.; Feng, Yun; Gould, Ty; Kirby, Christina A.; Stams, Travis; Waters, Nigel J.; Shao, WenlinJournal of Medicinal Chemistry (2013), 56 (17), 7049-7059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members is reprted. The utilization of lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive the evaluation of this series is demonstrated. These efforts led to a series of selective, cell-active compds. with soly., physicochem., and in vitro properties suitable for further optimization.(b) Shultz, M. D.; Cheung, A. K.; Kirby, C. A.; Firestone, B.; Fan, J.; Chen, C. H.; Chen, Z.; Chin, D. N.; Dipietro, L.; Fazal, A.; Feng, Y.; Fortin, P. D.; Gould, T.; Lagu, B.; Lei, H.; Lenoir, F.; Majumdar, D.; Ochala, E.; Palermo, M. G.; Pham, L.; Pu, M.; Smith, T.; Stams, T.; Tomlinson, R. C.; Toure, B. B.; Visser, M.; Wang, R. M.; Waters, N. J.; Shao, W. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J. Med. Chem. 2013, 56, 6495– 6511, DOI: 10.1021/jm400807n[ACS Full Text], [CAS], Google Scholar163bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtV2msbfE&md5=db3f1a471ca757e0219a5175c5017e9bIdentification of NVP-TNKS656: The Use of Structure-Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase InhibitorShultz, Michael D.; Cheung, Atwood K.; Kirby, Christina A.; Firestone, Brant; Fan, Jianmei; Chen, Christine Hiu-Tung; Chen, Zhouliang; Chin, Donovan N.; DiPietro, Lucian; Fazal, Aleem; Feng, Yun; Fortin, Pascal D.; Gould, Ty; Lagu, Bharat; Lei, Huangshu; Lenoir, Francois; Majumdar, Dyuti; Ochala, Etienne; Palermo, M. G.; Pham, Ly; Pu, Minying; Smith, Troy; Stams, Travis; Tomlinson, Ronald C.; Toure, B. Barry; Visser, Michael; Wang, Run Ming; Waters, Nigel J.; Shao, WenlinJournal of Medicinal Chemistry (2013), 56 (16), 6495-6511CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodn. signature of binding, highly favorable physicochem. properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.
- 164Jiang, Z. Y.; Xu, L. L.; Lu, M. C.; Chen, Z. Y.; Yuan, Z. W.; Xu, X. L.; Guo, X. K.; Zhang, X. J.; Sun, H. P.; You, Q. D. Structure-activity and structure-property relationship and exploratory in vivo evaluation of the nanomolar Keap1-Nrf2 protein-protein interaction inhibitor. J. Med. Chem. 2015, 58, 6410– 6421, DOI: 10.1021/acs.jmedchem.5b00185[ACS Full Text], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12ksb7N&md5=458f0a612c34156a137759d99b741e3aStructure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction InhibitorJiang, Zheng-Yu; Xu, Li-Li; Lu, Meng-Chen; Chen, Zhi-Yun; Yuan, Zhen-Wei; Xu, Xiao-Li; Guo, Xiao-Ke; Zhang, Xiao-Jin; Sun, Hao-Peng; You, Qi-DongJournal of Medicinal Chemistry (2015), 58 (16), 6410-6421CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure-activity and structure-property relationships of the ring systems to improve the drug-like properties. Compd. 18e (I), which bore p-acetamido substituents on the side chain Ph rings, was the best choice for balancing PPI inhibition activity, physicochem. properties, and cellular Nrf2 activity. Cell-based expts. with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo expt. was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.
- 165(a) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010, 1, 435– 449, DOI: 10.1021/cn100008c[ACS Full Text.], [CAS], Google Scholar165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVejtr8%253D&md5=e94998f65a420be6ee4dec4a987cb983Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike PropertiesWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.(b) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem. Neurosci. 2016, 7, 767– 775, DOI: 10.1021/acschemneuro.6b00029[ACS Full Text.], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksVSktbw%253D&md5=061c3aef6c88758cbaee1a2abb34796aCentral Nervous System Multiparameter Optimization Desirability: Application in Drug DiscoveryWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2016), 7 (6), 767-775CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Significant progress has been made in prospectively designing mols. using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the anal. reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochem. properties. The CNS MPO tool has helped to increase the percentage of compds. nominated for clin. development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the no. of compds. submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicol. into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compds. nominated for clin. development.(c) Wager, T. T.; Chappie, T.; Horton, D.; Chandrasekaran, R. Y.; Samas, B.; Dunn-Sims, E. R.; Hsu, C.; Nawreen, N.; Vanase-Frawley, M. A.; O’Connor, R. E.; Schmidt, C. J.; Dlugolenski, K.; Stratman, N. C.; Majchrzak, M. J.; Kormos, B. L.; Nguyen, D. P.; Sawant-Basak, A.; Mead, A. N. Dopamine D3/D2 receptor antagonist PF-4363467 attenuates opioid drug-seeking behavior without concomitant D2 side effects. ACS Chem. Neurosci. 2017, 8, 165– 177, DOI: 10.1021/acschemneuro.6b00297[ACS Full Text], [CAS], Google Scholar165chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1eltr7M&md5=abd6262987e08cb98b00d8057a52dc4fDopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side EffectsWager, Travis T.; Chappie, Thomas; Horton, David; Chandrasekaran, Ramalakshmi Y.; Samas, Brian; Dunn-Sims, Elizabeth R.; Hsu, Cathleen; Nawreen, Nawshaba; Vanase-Frawley, Michelle A.; O'Connor, Rebecca E.; Schmidt, Christopher J.; Dlugolenski, Keith; Stratman, Nancy C.; Majchrzak, Mark J.; Kormos, Bethany L.; Nguyen, David P.; Sawant-Basak, Aarti; Mead, Andy N.ACS Chemical Neuroscience (2017), 8 (1), 165-177CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Dopamine receptor antagonism is a compelling mol. target for the treatment of a range of psychiatric disorders, including substance use disorders. From the authors' corporate compd. file the authors identified a structurally unique D3 receptor (D3R) antagonist scaffold, PNU-177864. Through a hybrid approach, the authors merged key pharmacophore elements from PNU-177864 and D3 agonist PF-592379 to yield the novel D3R/D2R antagonist PF-4363467. PF-4363467 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addn. to good physicochem. properties, PF-4363467 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.2 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R vs. other biogenic amine receptors. In vivo, PF-4363467 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not obsd. despite high D2 receptor occupancy (RO) in rodents, suggesting that compd. PF-4363467 has a unique in vivo profile. Collectively, the authors' data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.
- 166Vilums, M.; Zweemer, A. J.; Yu, Z.; de Vries, H.; Hillger, J. M.; Wapenaar, H.; Bollen, I. A.; Barmare, F.; Gross, R.; Clemens, J.; Krenitsky, P.; Brussee, J.; Stamos, D.; Saunders, J.; Heitman, L. H.; Ijzerman, A. P. Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. J. Med. Chem. 2013, 56, 7706– 7714, DOI: 10.1021/jm4011737[ACS Full Text], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeksbvM&md5=9cd60706c51fa9d58b7674d069d21433Structure-Kinetic Relationships-An Overlooked Parameter in Hit-to-Lead Optimization: A Case of Cyclopentylamines as Chemokine Receptor 2 AntagonistsVilums, Maris; Zweemer, Annelien J. M.; Yu, Zhiyi; de Vries, Henk; Hillger, Julia M.; Wapenaar, Hannah; Bollen, Ilse A. E.; Barmare, Farhana; Gross, Raymond; Clemens, Jeremy; Krenitsky, Paul; Brussee, Johannes; Stamos, Dean; Saunders, John; Heitman, Laura H.; Ijzerman, Adriaan P.Journal of Medicinal Chemistry (2013), 56 (19), 7706-7714CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Preclin. models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a crit. role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clin. trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition assocn. assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compd. 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compd. 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.
- 167Yu, Z.; van Veldhoven, J. P.; Louvel, J.; t Hart, I. M.; Rook, M. B.; van der Heyden, M. A.; Heitman, L. H.; IJzerman, A. P. Structure-affinity relationships (SARs) and Structure-kinetics relationships (SKRs) of Kv11.1 blockers. J. Med. Chem. 2015, 58, 5916– 5929, DOI: 10.1021/acs.jmedchem.5b00518[ACS Full Text], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFSjsLvM&md5=22a7767e7f14a39a8eed2c0422d5156eStructure-Affinity Relationships (SARs) and Structure-Kinetics Relationships (SKRs) of Kv11.1 BlockersYu, Zhiyi; van Veldhoven, Jacobus P. D.; Louvel, Julien; 't Hart, Ingrid M. E.; Rook, Martin B.; van der Heyden, Marcel A. G.; Heitman, Laura H.; IJzerman, Adriaan P.Journal of Medicinal Chemistry (2015), 58 (15), 5916-5929CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and assocn. rates, there were hardly any variations in the dissocn. rate consts. of these mols. with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel mols., in particular in the pyridinium class of compds., to further address this peculiar phenomenon. We found mols. with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a kon-koff-KD kinetic map for all compds. and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of Kv11.1 blockers. Addnl., two representative compds. (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict Kv11.1-mediated cardiotoxicity.
- 168Rai, G.; Brimacombe, K. R.; Mott, B. T.; Urban, D. J.; Hu, X.; Yang, S. M.; Lee, T. D.; Cheff, D. M.; Kouznetsova, J.; Benavides, G. A.; Pohida, K.; Kuenstner, E. J.; Luci, D. K.; Lukacs, C. M.; Davies, D. R.; Dranow, D. M.; Zhu, H.; Sulikowski, G.; Moore, W. J.; Stott, G. M.; Flint, A. J.; Hall, M. D.; Darley-Usmar, V. M.; Neckers, L. M.; Dang, C. V.; Waterson, A. G.; Simeonov, A.; Jadhav, A.; Maloney, D. J. Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH). J. Med. Chem. 2017, 60, 9184– 9204, DOI: 10.1021/acs.jmedchem.7b00941[ACS Full Text], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOkurfP&md5=a2df6432e54403e18abc6078fc30e692Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)Rai, Ganesha; Brimacombe, Kyle R.; Mott, Bryan T.; Urban, Daniel J.; Hu, Xin; Yang, Shyh-Ming; Lee, Tobie D.; Cheff, Dorian M.; Kouznetsova, Jennifer; Benavides, Gloria A.; Pohida, Katie; Kuenstner, Eric J.; Luci, Diane K.; Lukacs, Christine M.; Davies, Douglas R.; Dranow, David M.; Zhu, Hu; Sulikowski, Gary; Moore, William J.; Stott, Gordon M.; Flint, Andrew J.; Hall, Matthew D.; Darley-Usmar, Victor M.; Neckers, Leonard M.; Dang, Chi V.; Waterson, Alex G.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.Journal of Medicinal Chemistry (2017), 60 (22), 9184-9204CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report the discovery and medicinal chem. optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quant. high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compds. with potent enzymic and cell-based inhibition of LDH enzymic activity. Lead compds. such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate prodn., and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compds. was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was detd. via SPR. Anal. of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metab. target.
- 169Brough, P. A.; Baker, L.; Bedford, S.; Brown, K.; Chavda, S.; Chell, V.; D’Alessandro, J.; Davies, N. G.; Davis, B.; Le Strat, L.; Macias, A. T.; Maddox, D.; Mahon, P. C.; Massey, A. J.; Matassova, N.; McKenna, S.; Meissner, J. W.; Moore, J. D.; Murray, J. B.; Northfield, C. J.; Parry, C.; Parsons, R.; Roughley, S. D.; Shaw, T.; Simmonite, H.; Stokes, S.; Surgenor, A.; Stefaniak, E.; Robertson, A.; Wang, Y.; Webb, P.; Whitehead, N.; Wood, M. Application of off-rate screening in the identification of novel pan-isoform inhibitors of pyruvate dehydrogenase kinase. J. Med. Chem. 2017, 60, 2271– 2286, DOI: 10.1021/acs.jmedchem.6b01478[ACS Full Text], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1agt7o%253D&md5=9727ca9e73096f63bbbb604c534155d8Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase KinaseBrough, Paul A.; Baker, Lisa; Bedford, Simon; Brown, Kirsten; Chavda, Seema; Chell, Victoria; D'Alessandro, Jalanie; Davies, Nicholas G. M.; Davis, Ben; Le Strat, Loic; Macias, Alba T.; Maddox, Daniel; Mahon, Patrick C.; Massey, Andrew J.; Matassova, Natalia; McKenna, Sean; Moore, Jonathan D.; Murray, James B.; Northfield, Christopher J.; Parry, Charles; Parsons, Rachel; Roughley, Stephen D.; Shaw, Terry; Simmonite, Heather; Stokes, Stephen; Surgenor, Allan; Stefaniak, Emma; Robertson, Alan; Wang, Yikang; Webb, Paul; Whitehead, Neil; Wood, MikeJournal of Medicinal Chemistry (2017), 60 (6), 2271-2286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Libraries of non-purified resorcinol amide derivs. were screened by surface plasmon resonance (SPR) to det. the binding dissocn. const. (off-rate, kd) for compds. binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
- 170Klebe, G. Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discovery 2015, 14, 95– 110, DOI: 10.1038/nrd4486[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVemtr4%253D&md5=c2e12760623de81335ce252cb804c602Applying thermodynamic profiling in lead finding and optimizationKlebe, GerhardNature Reviews Drug Discovery (2015), 14 (2), 95-110CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Small-mol. drug discovery involves the optimization of various physicochem. properties of a ligand, particularly its binding affinity for its target receptor (or receptors). In recent years, there has been growing interest in using thermodn. profiling of ligand-receptor interactions in order to select and optimize those ligands that might be most likely to become drug candidates with desirable physicochem. properties. The thermodn. of binding is influenced by multiple factors, including hydrogen bonding and hydrophobic interactions, desolvation, residual mobility, dynamics and the local water structure. This article discusses key issues in understanding the effects of these factors and applying this knowledge in drug discovery.
- 171Cusack, K. P.; Wang, Y.; Hoemann, M. Z.; Marjanovic, J.; Heym, R. G.; Vasudevan, A. Design strategies to address kinetics of drug binding and residence time. Bioorg. Med. Chem. Lett. 2015, 25, 2019– 2027, DOI: 10.1016/j.bmcl.2015.02.027[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktVCjsLg%253D&md5=c3735de36094915768dbecc7472917d4Design strategies to address kinetics of drug binding and residence timeCusack, Kevin P.; Wang, Ying; Hoemann, Michael Z.; Marjanovic, Jasmina; Heym, Roland G.; Vasudevan, AnilBioorganic & Medicinal Chemistry Letters (2015), 25 (10), 2019-2027CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The kinetics of drug binding and drug residence time are recognized to be important in the clin. effectiveness of drug candidates. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concns. of drug have been notably reduced through elimination routes. Hence, if selective for target, long residence times can increase the duration of drug efficacy in vivo and can significantly diminish the potential for off-target-mediated toxicities. Furthermore, a compd. with a slower dissocn. rate may allow a reduced dosing schedule relative to a compd. with a rapid dissocn. rate. Factors contributing to long residence time that could be useful to medicinal chemists in the prospective design of compds. with long residence times will be discussed in this perspective. Particular emphasis will be on case studies highlighting how kinetics can be measured, modulated based on supporting structure kinetic relationships and whether these effects are translatable into man.
- 172Buch, I.; Giorgino, T.; De Fabritiis, G. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 10184– 10189, DOI: 10.1073/pnas.1103547108[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXot1egu78%253D&md5=40fdd0ec62da71c0f11d57731ee518a1Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulationsBuch, Ignasi; Giorgino, Toni; De Fabritiis, GianniProceedings of the National Academy of Sciences of the United States of America (2011), 108 (25), 10184-10189, S10184/1-S10184/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The understanding of protein-ligand binding is of crit. importance for biomedical research, yet the process itself has been very difficult to study because of its intrinsically dynamic character. Here, we have been able to quant. reconstruct the complete binding process of the enzyme-inhibitor complex trypsin-benzamidine by performing 495 mol. dynamics simulations of free ligand binding of 100 ns each, 187 of which produced binding events with an rmsd less than 2 Å compared to the crystal structure. The binding paths obtained are able to capture the kinetic pathway of the inhibitor diffusing from solvent (SO) to the bound (S4) state passing through two metastable intermediate states S2 and S3. Rather than directly entering the binding pocket the inhibitor appears to roll on the surface of the protein in its transition between S3 and the final binding pocket, whereas the transition between S2 and the bound pose requires rediffusion to S3. An estn. of the std. free energy of binding gives ΔG° = -5.2 0.4 kcal/mol (cf. the exptl. value -6.2 kcal/mol), and a two-states kinetic model kon = (1.5 ± 0.2) × 108 M-1 s-1 and koff = (9.5 ± 3.3) × 104 s-1 for unbound to bound transitions. The ability to reconstruct by simple diffusion the binding pathway of an enzyme-inhibitor binding process demonstrates the predictive power of unconventional high-throughput mol. simulations. Moreover, the methodol. is directly applicable to other mol. systems and thus of general interest in biomedical and pharmaceutical research.
- 173Perricone, U.; Gulotta, M. R.; Lombino, J.; Parrino, B.; Cascioferro, S.; Diana, P.; Cirrincione, G.; Padova, A. An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge. MedChemComm 2018, 9, 920– 936, DOI: 10.1039/C8MD00166A[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnvFemtrc%253D&md5=31f1de36caeaff89594e2b365052ea20An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challengePerricone, Ugo; Gulotta, Maria Rita; Lombino, Jessica; Parrino, Barbara; Cascioferro, Stella; Diana, Patrizia; Cirrincione, Girolamo; Padova, AlessandroMedChemComm (2018), 9 (6), 920-936CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Mol. dynamics (MD) has become increasingly popular due to the development of hardware and software solns. and the improvement in algorithms, which allowed researchers to scale up calcns. in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile anal. over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calcg. some kinetic and thermodn. parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimization of the mol. structure of a lead compd. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognized as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimize small mols. and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small mols. or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.
- 174Mollica, L.; Theret, I.; Antoine, M.; Perron-Sierra, F.; Charton, Y.; Fourquez, J. M.; Wierzbicki, M.; Boutin, J. A.; Ferry, G.; Decherchi, S.; Bottegoni, G.; Ducrot, P.; Cavalli, A. Molecular dynamics simulations and kinetic measurements to estimate and predict protein-ligand residence times. J. Med. Chem. 2016, 59, 7167– 7176, DOI: 10.1021/acs.jmedchem.6b00632[ACS Full Text], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFersrfE&md5=cbe23fde2bf0640f77501c0160821a68Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence TimesMollica, Luca; Theret, Isabelle; Antoine, Mathias; Perron-Sierra, Francoise; Charton, Yves; Fourquez, Jean-Marie; Wierzbicki, Michel; Boutin, Jean A.; Ferry, Gilles; Decherchi, Sergio; Bottegoni, Giovanni; Ducrot, Pierre; Cavalli, AndreaJournal of Medicinal Chemistry (2016), 59 (15), 7167-7176CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Exptl. approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force mol. dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodol. to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with exptl. kinetics measurements and X-ray crystallog., promptly checking the protocol's reliability by directly comparing computational predictions and exptl. measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estg. and predicting drug residence times.
- 175Krimmer, S. G.; Cramer, J.; Betz, M.; Fridh, V.; Karlsson, R.; Heine, A.; Klebe, G. Rational design of thermodynamic and kinetic binding profiles by optimizing surface water networks coating protein-bound ligands. J. Med. Chem. 2016, 59, 10530– 10548, DOI: 10.1021/acs.jmedchem.6b00998[ACS Full Text], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVCjsL%252FN&md5=37092339ddcbe5a1ec6a10572b1a3213Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound LigandsKrimmer, Stefan G.; Cramer, Jonathan; Betz, Michael; Fridh, Veronica; Karlsson, Robert; Heine, Andreas; Klebe, GerhardJournal of Medicinal Chemistry (2016), 59 (23), 10530-10548CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water mols. resulted in enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, the authors optimized the series by designing tailored P2' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resoln. crystallog., microcalorimetry and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.
- 176Nasief, N. N.; Tan, H.; Kong, J.; Hangauer, D. Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(−) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes. J. Med. Chem. 2012, 55, 8283– 8302, DOI: 10.1021/jm300472k[ACS Full Text], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SlsrjL&md5=8f77eb36b73bf36f914aa0de1d338ddeWater Mediated Ligand Functional Group Cooperativity: The Contribution of a Methyl Group to Binding Affinity is Enhanced by a COO- Group Through Changes in the Structure and Thermodynamics of the Hydration Waters of Ligand-Thermolysin ComplexesNasief, Nader N.; Tan, Hongwei; Kong, Jing; Hangauer, DavidJournal of Medicinal Chemistry (2012), 55 (19), 8283-8302CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ligand functional groups can modulate the contributions of one another to the ligand-protein binding thermodn., producing either pos. or neg. cooperativity. Data presented for four thermolysin phosphonamidate inhibitors demonstrate that the differential binding free energy and enthalpy caused by replacement of a H with a Me group, which binds in the well-hydrated S2' pocket, are more favorable in presence of a ligand carboxylate. The differential entropy is however less favorable. Dissection of these differential thermodn. parameters, X-ray crystallog., and d.-functional theory calcns. suggest that these cooperativities are caused by variations in the thermodn. of the complex hydration shell changes accompanying the H→Me replacement. Specifically, the COO- reduces both the enthalpic penalty and the entropic advantage of displacing water mols. from the S2' pocket and causes a subsequent acquisition of a more enthalpically, less entropically, favorable water network. This study contributes to understanding the important role water plays in ligand-protein binding.
- 177Liu, L. Efficient hit and lead compound evaluation strategy based on off-rate screening by surface plasmon resonance. J. Med. Chem. 2014, 57, 2843– 2844, DOI: 10.1021/jm5003815[ACS Full Text], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkslamu74%253D&md5=ed9a35d3ddf07415ad543bc7857f2243Efficient Hit and Lead Compound Evaluation Strategy Based on Off-Rate Screening by Surface Plasmon ResonanceLiu, LiuJournal of Medicinal Chemistry (2014), 57 (7), 2843-2844CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The time-consuming and labor intensive compd. sepn. and purifn. process before they can be evaluated have been the bottleneck steps of novel drug discovery. A new screening strategy that can evaluate crude reaction mixts. without sepn. and purifn. by detg. dissocn. rate consts. of compds. in crude reaction mixts. was developed and validated by scientists from the Vernalis. This new strategy will significantly improve the efficiency of early stages in drug discovery.
- 178Murray, J. B.; Roughley, S. D.; Matassova, N.; Brough, P. A. Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products. J. Med. Chem. 2014, 57, 2845– 2850, DOI: 10.1021/jm401848a[ACS Full Text], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisVWguro%253D&md5=d3744f00df767e349024641e876e8100Off-Rate Screening (ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction ProductsMurray, James B.; Roughley, Stephen D.; Matassova, Natalia; Brough, Paul A.Journal of Medicinal Chemistry (2014), 57 (7), 2845-2850CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The dissocn. rate const. kd (off-rate) is the component of ligand-protein binding with the most significant potential to enhance compd. potency. Here we provide theor. and empirical data to show that this parameter can be detd. accurately from unpurified reaction products contg. designed test compds. This screening protocol is amenable to parallel chem., provides efficiencies of time and materials, and complements existing methodologies for the hit-to-lead phase in fragment-based drug discovery.
- 179Spagnuolo, L. A.; Eltschkner, S.; Yu, W.; Daryaee, F.; Davoodi, S.; Knudson, S. E.; Allen, E. K.; Merino, J.; Pschibul, A.; Moree, B.; Thivalapill, N.; Truglio, J. J.; Salafsky, J.; Slayden, R. A.; Kisker, C.; Tonge, P. J. Evaluating the contribution of transition-state destabilization to changes in the residence time of triazole-based InhA inhibitors. J. Am. Chem. Soc. 2017, 139, 3417– 3429, DOI: 10.1021/jacs.6b11148[ACS Full Text], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeqs7g%253D&md5=46a5a148f16f540cb77889cf90a46d94Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA InhibitorsSpagnuolo, Lauren A.; Eltschkner, Sandra; Yu, Weixuan; Daryaee, Fereidoon; Davoodi, Shabnam; Knudson, Susan E.; Allen, Eleanor K. H.; Merino, Jonathan; Pschibul, Annica; Moree, Ben; Thivalapill, Neil; Truglio, James J.; Salafsky, Joshua; Slayden, Richard A.; Kisker, Caroline; Tonge, Peter J.Journal of the American Chemical Society (2017), 139 (9), 3417-3429CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A crit. goal of lead compd. selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodn. and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, the authors predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-contg. di-Ph ether with an increased residence time on InhA due to transition state destabilization rather than ground state stabilization. In the present work, the authors have evaluated the inhibition of InhA by 14 triazole-based di-Ph ethers and used a combination of enzyme kinetics and x-ray crystallog. to generate a structure-kinetic relationship (SKR) for time-dependent binding. The authors show that the triazole motif slows the rate of formation for the final drug-target complex by up to three orders of magnitude. In addn., the authors identify a novel inhibitor with a residence time on InhA of 220 min which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.
- 180Kokh, D. B.; Amaral, M.; Bomke, J.; Grädler, U.; Musil, D.; Buchstaller, H. P.; Dreyer, M. K.; Frech, M.; Lowinski, M.; Vallee, F.; Bianciotto, M.; Rak, A.; Wade, R. C. Estimation of drug-target residence times by τ-random acceleration molecular dynamics simulations. J. Chem. Theory Comput. 2018, 14, 3859– 3869, DOI: 10.1021/acs.jctc.8b00230[ACS Full Text], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpslWqt70%253D&md5=b2550dd6777bb7be3b63176c5e74fec5Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics SimulationsKokh, Daria B.; Amaral, Marta; Bomke, Joerg; Graedler, Ulrich; Musil, Djordje; Buchstaller, Hans-Peter; Dreyer, Matthias K.; Frech, Matthias; Lowinski, Maryse; Vallee, Francois; Bianciotto, Marc; Rak, Alexey; Wade, Rebecca C.Journal of Chemical Theory and Computation (2018), 14 (7), 3859-3869CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration mol. dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissocn. mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compds. and less than 2.0τ within congeneric series. Anal. of dissocn. trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.
- 181Cummins, D. J.; Bell, M. A. Integrating Everything: The molecule selection toolkit, a system for compound prioritization in drug discovery. J. Med. Chem. 2016, 59, 6999– 7010, DOI: 10.1021/acs.jmedchem.5b01338[ACS Full Text], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjs12itbg%253D&md5=59b06f02ef4f2997eeff69bcf5f8ce59Integrating Everything: The Molecule Selection Toolkit, a System for Compound Prioritization in Drug DiscoveryCummins, David J.; Bell, Michael A.Journal of Medicinal Chemistry (2016), 59 (15), 6999-7010CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In recent years there have been numerous papers on the topic of multiattribute optimization in pharmaceutical discovery chem., applied to compd. prioritization. Many solns. proposed are static in nature; fixed functions are proposed for general purpose use. As needs change, these are modified and proposed as the latest enhancement. Rather than producing one more set of static functions, this work proposes a flexible approach to prioritizing compds. Most published approaches also lack a design component. This work describes a comprehensive implementation that includes predictive modeling, multiattribute optimization, and modern statistical design. This gives a complete package for effectively prioritizing compds. for lead generation and lead optimization. The approach described has been used at our company in various stages of discovery since 2001. An adaptable system alleviates the need for different static solns., each of which inevitably must be updated as the needs of a project change.
- 182McEnaney, P. J.; Parker, C. G.; Zhang, A. X.; Spiegel, D. A. Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease. ACS Chem. Biol. 2012, 7, 1139– 1151, DOI: 10.1021/cb300119g[ACS Full Text], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpsl2isr0%253D&md5=17dcc667dae735c02b1f35a4cd6139c9Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human DiseaseMcEnaney, Patrick J.; Parker, Christopher G.; Zhang, Andrew X.; Spiegel, David A.ACS Chemical Biology (2012), 7 (7), 1139-1151CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A review. Synthetic immunol., the development of synthetic systems capable of modulating and/or manipulating immunol. functions, represents an emerging field of research with manifold possibilities. One focus of this area has been to create low mol. wt. synthetic species, called antibody-recruiting mols. (ARMs), which are capable of enhancing antibody binding to disease-relevant cells or viruses, thus leading to their immune-mediated clearance. This article provides a thorough discussion of contributions in this area, beginning with the history of small-mol.-based technologies for modulating antibody recognition, followed by a systematic review of the various applications of ARM-based strategies. Thus, we describe ARMs capable of targeting cancer, bacteria, and viral pathogens, along with some of the scientific discoveries that have resulted from their development. Research in this area underscores the many exciting possibilities at the interface of org. chem. and immunobiol. and is positioned to advance both basic and clin. science in the years to come.
- 183Casi, G.; Neri, D. Antibody-drug conjugates and small molecule-drug conjugates: opportunities and challenges for the development of selective anticancer cytotoxic agents. J. Med. Chem. 2015, 58, 8751– 8761, DOI: 10.1021/acs.jmedchem.5b00457[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVagurzO&md5=24614e4825cbfe408e0b875db1826e68Antibody-Drug Conjugates and Small Molecule-Drug Conjugates: Opportunities and Challenges for the Development of Selective Anticancer Cytotoxic AgentsCasi, Giulio; Neri, DarioJournal of Medicinal Chemistry (2015), 58 (22), 8751-8761CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Conventional cancer chemotherapy heavily relies on the use of cytotoxic agents, which typically do not preferentially localize at the tumor site and cause toxicity to normal organs, preventing dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the neoplastic mass. For many years, the availability of ligands, capable of selective internalization into tumor cells, has been considered to be an essential requirement for the development of targeted cytotoxics. This assumption, however, has recently been challenged on the basis of therapeutic data obtained with noninternalizing drug conjugates. Moreover, quant. evaluations of the tumor targeting properties of antibodies and of small org. ligands have provided new insights for the implementation of optimal strategies for the development of targeted cytotoxics. In this article, we highlight opportunities and challenges assocd. with the clin. and industrial development of antibody-drug conjugates and small mol.-drug conjugates for cancer therapy.
- 184Murelli, R. P.; Zhang, A. X.; Michel, J.; Jorgensen, W. L.; Spiegel, D. A. Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer. J. Am. Chem. Soc. 2009, 131, 17090– 17092, DOI: 10.1021/ja906844e[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlKjsrvE&md5=1e6c183dc23acaa79b85c83835ceeb4fChemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules that Target Prostate CancerMurelli, Ryan P.; Zhang, Andrew X.; Michel, Julien; Jorgensen, William L.; Spiegel, David A.Journal of the American Chemical Society (2009), 131 (47), 17090-17092CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biol. evaluation of a class of bifunctional small mols. called antibody-recruiting mols. targeting prostate cancer (ARM-Ps) that enhance the recognition of prostate cancer cells by the human immune system. ARM-P derivs. were designed rationally via the computational anal. of crystallog. data, and we demonstrate here that these materials are able to (1) bind prostate-specific membrane antigen (PSMA) with high affinity (high pM to low nM), (2) template the formation of ternary complexes of anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, and (3) mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells. This manuscript describes the application of fundamental chem. principles to the design of a novel class of mols. with high therapeutic potential. We believe that this general small-mol.-based strategy could give rise to novel directions in treating cancer and other diseases.
- 185(a) Parker, C. G.; Domaoal, R. A.; Anderson, K. S.; Spiegel, D. A. An antibody-recruiting small molecule that targets HIV gp120. J. Am. Chem. Soc. 2009, 131, 16392– 16394, DOI: 10.1021/ja9057647[ACS Full Text.], [CAS], Google Scholar185ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1yjtLvN&md5=1c8913f7b4ac456ac7ccf2138f29fe0aAn Antibody-Recruiting Small Molecule That Targets HIV gp120Parker, Christopher G.; Domaoal, Robert A.; Anderson, Karen S.; Spiegel, David A.Journal of the American Chemical Society (2009), 131 (45), 16392-16394CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)HIV/AIDS is a global pandemic for which new treatment strategies are desperately needed. The authors have designed a novel small mol.I [X = (CH2CH2O)5, Y = = (CH2CH2O)3], designated as ARM-H, that has the potential to interfere with HIV survival through two mechanisms: (1) by recruiting antibodies to gp120-expressing virus particles and infected human cells, thus enhancing their uptake and destruction by the human immune system, and (2) by binding the viral glycoprotein gp120, inhibiting its interaction with the human protein CD4 and preventing virus entry. Here the authors demonstrate that ARM-H I is capable of simultaneously binding gp120, a component of the Env surface viral glycoprotein (found on the surface of both HIV and virus-infected cells) and anti-2,4-dinitrophenyl antibodies (already present in the human bloodstream). The ternary complex formed between the antibody, ARM-H I, and gp120 is immunol. active and leads to the complement-mediated destruction of Env-expressing cells. Furthermore, ARM-H prevents virus entry into human T-cells and should therefore be capable of inhibiting virus replication through two mutually reinforcing mechanisms (inhibition of virus entry and antibody-mediated killing). These studies demonstrate the viable anti-HIV activity of antibody-recruiting small mols. and have the potential to initiate novel paradigms in HIV treatment.(b) Parker, C. G.; Dahlgren, M. K.; Tao, R. N.; Li, D. T.; Douglass, E. F., Jr.; Shoda, T.; Jawanda, N.; Spasov, K. A.; Lee, S.; Zhou, N.; Domaoal, R. A.; Sutton, R. E.; Anderson, K. S.; Jorgensen, W. L.; Krystal, M.; Spiegel, D. A. Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules. Chem. Sci. 2014, 5, 2311– 2317, DOI: 10.1039/C4SC00484A[Crossref], [PubMed], [CAS], Google Scholar185bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsFSqs7s%253D&md5=9ecc41d0ae77c6f0a5804d3b74127687Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting moleculesParker, Christopher G.; Dahlgren, Markus K.; Tao, Ran N.; Li, Don T.; Douglass, Eugene F.; Shoda, Takuji; Jawanda, Navneet; Spasov, Krasimir A.; Lee, Sangil; Zhou, Nannan; Domaoal, Robert A.; Sutton, Richard E.; Anderson, Karen S.; Krystal, Mark; Jorgensen, William L.; Spiegel, David A.Chemical Science (2014), 5 (6), 2311-2317CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Here we report on the structure-based optimization of antibody-recruiting mols. targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chem., biochem. and cellular assay anal., and computation. Our findings have afforded an optimized analog of ARM-H, which is ∼1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported deriv. Furthermore, computational anal., taken together with exptl. data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple distinct binding modes in interacting with gp120. These results are likely to prove enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.
- 186Genady, A. R.; Janzen, N.; Banevicius, L.; El-Gamal, M.; El-Zaria, M. E.; Valliant, J. F. Preparation and evaluation of radiolabeled antibody recruiting small molecules that target prostate-specific membrane antigen for combined radiotherapy and immunotherapy. J. Med. Chem. 2016, 59, 2660– 2673, DOI: 10.1021/acs.jmedchem.5b01881[ACS Full Text], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVektL4%253D&md5=1fa1a23752e81b3732b9a8a6ffcdfc5ePreparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and ImmunotherapyGenady, Afaf R.; Janzen, Nancy; Banevicius, Laura; El-Gamal, Mahmoud; El-Zaria, Mohamed E.; Valliant, John F.Journal of Medicinal Chemistry (2016), 59 (6), 2660-2673CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small mol. (ARM) was detd. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compd. (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analog showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, resp. The radiolabeled analog was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compds. reported represent the first examples of small mols. developed specifically for combination immunotherapy and radiotherapy for prostate cancer.
- 187Liu, Z.; Chen, X. Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy. Chem. Soc. Rev. 2016, 45, 1432– 1456, DOI: 10.1039/C5CS00158G[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XovVKkug%253D%253D&md5=6cbd8231b0f3dcdd776d464a835d535eSimple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapyLiu, Zhibo; Chen, XiaoyuanChemical Society Reviews (2016), 45 (5), 1432-1456CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-mol. wt. drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technol. (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chem. strategies of developing HSA binding mols. for coupling with drug mols. Moreover, we also concisely condense the recent progress of the most important clin. applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding.
- 188Matos, M. J. Learning from nature: the role of albumin in drug delivery. Future Med. Chem. 2018, 10, 983– 985, DOI: 10.4155/fmc-2018-0053[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt1GnsLw%253D&md5=5ba8158eaf7686844ac868f0bcff6c26Learning from nature: the role of albumin in drug deliveryMatos, Maria J.Future Medicinal Chemistry (2018), 10 (9), 983-985CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)Graphical Abstr. :.
- 189Kratz, F.; Muller-Driver, R.; Hofmann, I.; Drevs, J.; Unger, C. A novel macromolecular prodrug concept exploiting endogenous serum albumin as a drug carrier for cancer chemotherapy. J. Med. Chem. 2000, 43, 1253– 1256, DOI: 10.1021/jm9905864[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhsFyhtLw%253D&md5=6a49fb71aa60db8d4fd949592fc8414eA Novel Macromolecular Prodrug Concept Exploiting Endogenous Serum Albumin as a Drug Carrier for Cancer ChemotherapyKratz, Felix; Mueller-Driver, Ralph; Hofmann, Inga; Drevs, Joachim; Unger, ClemensJournal of Medicinal Chemistry (2000), 43 (7), 1253-1256CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A maleimide phenylacetylhydrazone deriv. of doxorubicin (I) bound preferentially to endogenous serum albumin after incubation with human blood plasma or direct i.v. injection into mice. Preincubation studies with a maleimide compd. and coupling reactions with native serum albumin indicate that I binds to cytosine-34 of albumin which is an attractive binding site in blood plasma due to the fact that other major plasma proteins do not contain free HS groups. In addn., I showed a superior antitumor effect in an animal tumor model, i.e., murine renal cell carcinoma (RENCA), when compared to free doxorubicin at equitoxic dose. This increase in therapeutic efficacy can be best explained by an enhanced permeability of tumor blood vessels for circulating proteins and a subsequent retention due to lacking lymphatic recovery system in tumor tissue. Studies in the RENCA model have shown that renal cell carcinomas are highly vascularized indicating that circulating macromols. such as serum albumin and resp. conjugates might be trapped by the vascular network of these tumors. Although a more detailed anal. of the in situ coupling of thiol-binding drug derivs. to endogenous albumin is warranted, it is believed that the outlined macromol. prodrug strategy is an attractive approach of altering the pharmacokinetic profile of clin. established anticancer drugs and increasing their therapeutic index.
- 190Jafari, N.; Ahmed, R.; Gloyd, M.; Bloomfield, J.; Britz-McKibbin, P.; Melacini, G. Allosteric sensing of fatty acid binding by NMR: application to human serum albumin. J. Med. Chem. 2016, 59, 7457– 7465, DOI: 10.1021/acs.jmedchem.6b00410[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyit7vN&md5=7ae3fd8dd89521b1a78b43d54f983087Allosteric Sensing of Fatty Acid Binding by NMR: Application to Human Serum AlbuminJafari, Naeimeh; Ahmed, Rashik; Gloyd, Melanie; Bloomfield, Jonathon; Britz-McKibbin, Philip; Melacini, GiuseppeJournal of Medicinal Chemistry (2016), 59 (16), 7457-7465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human serum albumin (HSA) serves not only as a physiol. oncotic pressure regulator and a ligand carrier but also as a biomarker for pathologies ranging from ischemia to diabetes. Moreover, HSA is a biopharmaceutical with a growing repertoire of putative clin. applications from hypovolemia to Alzheimer's disease. A key determinant of the physiol., diagnostic, and therapeutic functions of HSA is the amt. of long chain fatty acids (LCFAs) bound to HSA. Here, we propose to utilize 13C-oleic acid for the NMR-based assessment of albumin-bound LCFA concn. (CONFA). 13C-Oleic acid primes HSA for a LCFA-dependent allosteric transition that modulates the frequency sepn. between the two main 13C NMR peaks of HSA-bound oleic acid (ΔνAB). On the basis of ΔνAB, the overall [12C-LCFA]Tot/[HSA]Tot ratio is reproducibly estd. in a manner that is only minimally sensitive to glycation, albumin concn., or redox potential, unlike other methods to quantify HSA-bound LCFAs such as the albumin-cobalt binding assay.
- 191Shechter, Y.; Tsubery, H.; Fridkin, M. N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl](3)-gentamicin C(1) is a long-acting prodrug derivative. J. Med. Chem. 2002, 45, 4264– 4270, DOI: 10.1021/jm020042t[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtVylsr4%253D&md5=802cd413f5fe1112d4e5da8551fb6641N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl]3-gentamicin C1 Is a Long-Acting Prodrug DerivativeShechter, Yoram; Tsubery, Haim; Fridkin, MatiJournal of Medicinal Chemistry (2002), 45 (19), 4264-4270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Most low-mol.-wt. drugs are short-lived species in the circulatory system, being rapidly eliminated by glomerular filtration in the kidney. However, binding to human serum albumin (HSA) can slow clearance and prolong lifetime profile in vivo. In this study, we have engineered a gentamicin deriv. with affinity to albumin by linking three (2-sulfo)-9-fluorenylmethoxycarbonyl (FMS) to three amino groups of gentamicin C1. FMS3-gentamicin assocs. with HSA with a Ka value of (1.31 ± 0.2) × 105 M-1. It has less than 1% the antibacterial potency of native gentamicin. Upon incubation at pH 8.5 and 37 °C, the FMS moieties from FMS3-gentamicin undergo slow hydrolysis (t1/2 = 8.0 ± 0.2 h), leading to a linear regeneration of the antibacterial potency with a t1/2 value of 11 ± 0.7 h. FMS3-gentamicin is a long-lived species in the rat circulatory system. Following a single s.c. or i.v. administration, it maintains a prolonged pharmacokinetic profile with a peak and a "through" concn. of immuno/antibacterial active gentamicin exceeding 4-5 times the duration obtained by administered native gentamicin. To sum up, an approach aimed at elongating the lifetime of low-mol.-wt. drugs in vivo has been examd. here with gentamicin. Two to three FMS per mol of compd. are to be introduced to obtain an albumin assocg. affinity of Kd = 7.6-9.2 μM and, hence, to significantly extend the drug's lifetime in situ following administration. By use of this technol., the loss of pharmacol. potency with derivatization is of no consequence, since FMS moieties are hydrolyzed and activity is generated at physiol. conditions.
- 192Zheng, Y. R.; Suntharalingam, K.; Johnstone, T. C.; Yoo, H.; Lin, W.; Brooks, J. G.; Lippard, S. J. Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery. J. Am. Chem. Soc. 2014, 136, 8790– 8798, DOI: 10.1021/ja5038269[ACS Full Text], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptl2itrs%253D&md5=541fe9e155e3f4e2f8d6f61f3d81ee5aPt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug DeliveryZheng, Yao-Rong; Suntharalingam, Kogularamanan; Johnstone, Timothy C.; Yoo, Hyunsuk; Lin, Wei; Brooks, Jamar G.; Lippard, Stephen J.Journal of the American Chemical Society (2014), 136 (24), 8790-8798CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Albumin is the most abundant protein in human serum and drugs that are administered i.v. inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asym. functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliph. tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analog bearing a fluorophore conjugated to the succinate ligand confirmed that these compds. are reduced by biol. reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphol. following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extn. with octanol completely removes the prodrug from an aq. soln. of HSA. Construct 7 is robust and can be isolated following fast protein liq. chromatog. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of redn. of the prodrug by ascorbate. The lead compd. from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.
- 193Bech, E. M.; Martos-Maldonado, M. C.; Wismann, P.; Sorensen, K. K.; van Witteloostuijn, S. B.; Thygesen, M. B.; Vrang, N.; Jelsing, J.; Pedersen, S. L.; Jensen, K. J. Peptide half-life extension: divalent, small-molecule albumin interactions direct the systemic properties of glucagon-like peptide 1 (GLP-1) analogues. J. Med. Chem. 2017, 60, 7434– 7446, DOI: 10.1021/acs.jmedchem.7b00787[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OmsLnO&md5=8ed415888afd85068ac6a4b98090b69cPeptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide 1 (GLP-1) AnaloguesBech, Esben M.; Maldonado, Manuel C.; Wismann, Pernille; Soerensen, Kasper K.; van Witteloostuijn, Soeren Blok; Thygesen, Mikkel B.; Vrang, Niels; Jelsing, Jacob; Pedersen, Soeren L.; Jensen, Knud J.Journal of Medicinal Chemistry (2017), 60 (17), 7434-7446CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Noncovalent binding of biopharmaceuticals to human serum albumin protects against enzymic degrdn. and renal clearance. Herein, we investigated the effect of mono- or divalent small-mol. albumin binders for half-life extension of peptides. For proof-of-principle, the clin. relevant glucagon-like peptide 1 (GLP-1) was functionalized with diflunisal, indomethacin, or both. In vitro, all GLP-1 analogs had subnanomolar GLP-1 receptor potency. Surface plasmon resonance revealed that both small mols. were able to confer albumin affinity to GLP-1 and indicated that affinity is increased for divalent analogs. In lean mice, the divalent GLP-1 analogs were superior to monovalent analogs with respect to control of glucose homeostasis and suppression of food intake. Importantly, divalent GLP-1 analogs showed efficacy comparable to liraglutide, an antidiabetic GLP-1 analog that carries a long-chain fatty acid. Finally, pharmacokinetic investigations of a divalent GLP-1 analog demonstrated a promising gain in circulatory half-life and absorption time compared to its monovalent equiv.
- 194Kratz, F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin. Invest. Drugs 2007, 16, 855– 866, DOI: 10.1517/13543784.16.6.855[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltlOju7Y%253D&md5=88fec9cd817a4b10e54506d423eccd35DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trialsKratz, FelixExpert Opinion on Investigational Drugs (2007), 16 (6), 855-866CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)A review. The (6-maleimidocaproyl)hydrazone deriv. of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After i.v. administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clin. Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m2 when 75 mg/m2 of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.
- 195Zhang, H.; Wang, K.; Na, K.; Li, D.; Li, Z.; Zhao, D.; Zhong, L.; Wang, M.; Kou, L.; Luo, C.; Zhang, H.; Kan, Q.; Ding, H.; He, Z.; Sun, J. Striking a balance between carbonate/carbamate linkage bond- and reduction-sensitive disulfide bond-bearing linker for tailored controlled release: in situ covalent-albumin-binding gemcitabine prodrugs promote bioavailability and tumor accumulation. J. Med. Chem. 2018, 61, 4904– 4917, DOI: 10.1021/acs.jmedchem.8b00293[ACS Full Text], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps12ls7w%253D&md5=961b64121072b0f201faa7aa6854c933Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor AccumulationZhang, Huicong; Wang, Kuanglei; Na, Kexin; Li, Dan; Li, Zhenbao; Zhao, Dongyang; Zhong, Lu; Wang, Menglin; Kou, Longfa; Luo, Cong; Zhang, Haotian; Kan, Qiming; Ding, Huaiwei; He, Zhonggui; Sun, JinJournal of Medicinal Chemistry (2018), 61 (11), 4904-4917CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromol. prodrugs after i.v. administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, resp.), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, esp. the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.
- 197Chong, H.; Yao, X.; Zhang, C.; Cai, L.; Cui, S.; Wang, Y.; He, Y. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor. PLoS One 2012, 7, e32599, DOI: 10.1371/journal.pone.0032599[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvFaisLs%253D&md5=e56929dcfffbd80e1e1c1f333fb38934Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitorChong, Huihui; Yao, Xue; Zhang, Chao; Cai, Lifeng; Cui, Sheng; Wang, Youchun; He, YuxianPLoS One (2012), 7 (3), e32599CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophys. properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-neg. manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chem. modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.
- 198(a) Bohn, P.; Le Fur, N.; Hagues, G.; Costentin, J.; Torquet, N.; Papamicaël, C.; Marsais, F.; Levacher, V. Rational design of central selective acetylcholinesterase inhibitors by means of a ″bio-oxidisable prodrug″ strategy. Org. Biomol. Chem. 2009, 7, 2612– 2618, DOI: 10.1039/b903041g[Crossref], [PubMed], [CAS], Google Scholar.198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvV2nsLk%253D&md5=5a873be253275a9b0d93b4da8c56439aRational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategyBohn, Pierre; Le Fur, Nicolas; Hagues, Guillaume; Costentin, Jean; Torquet, Nicolas; Papamicael, Cyril; Marsais, Francis; Levacher, VincentOrganic & Biomolecular Chemistry (2009), 7 (12), 2612-2618CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)This work deals with the design of a "bio-oxidizable prodrug" strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects obsd. with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogs of rivastigmine. The key activation step of the prodrug involves an oxidn. of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the pos. charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biol. evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 106 nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 μM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogs of rivastigmine in quinoline series as appealing chem. tools for further in vivo development of this "bio-oxidizable prodrug" approach.(b) Bohn, P.; Gourand, F.; Papamicaël, C.; Ibazizène, M.; Dhilly, M.; Gembus, V.; Alix, F.; Ţînţaş, M. L.; Marsais, F.; Barré, L.; Levacher, V. Dihydroquinoline carbamate derivatives as ″bio-oxidizable″ prodrugs for brain delivery of acetylcholinesterase inhibitors: [11C] Radiosynthesis and biological evaluation. ACS Chem. Neurosci. 2015, 6, 737– 744, DOI: 10.1021/cn5003539[ACS Full Text.], [CAS], Google Scholar198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGks7k%253D&md5=e089ec639e23d630f228ac0b33090ed8Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [11C] Radiosynthesis and Biological EvaluationBohn, Pierre; Gourand, Fabienne; Papamicael, Cyril; Ibazizene, Meziane; Dhilly, Martine; Gembus, Vincent; Alix, Florent; Tintas, Mihaela-Liliana; Marsais, Francis; Barre, Louisa; Levacher, VincentACS Chemical Neuroscience (2015), 6 (5), 737-744CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biol. evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug I [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug II [IC50 = 20 nM (hAChE)] through central redox activation of I. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent pos. charge in II promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug I was developed for addnl. ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [11C]-I, while identification of [11C]-II and [11C]-III both accounts for central redox activation of I and pseudoirreversible inhibition of AChE, resp. Finally, Caco-2 permeability assays predicted metabolite III as a substrate for efflux transporters (P-gp interalia), suggesting that metabolite III might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.(c) Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M. L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. Donepezil-based central acetylcholinesterase inhibitors by means of a ″bio-oxidizable″ prodrug strategy: design, synthesis, and in vitro biological evaluation. J. Med. Chem. 2017, 60, 5909– 5926, DOI: 10.1021/acs.jmedchem.7b00702[ACS Full Text.], [CAS], Google Scholar198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpvFeju74%253D&md5=bd539cf43f39c5058b243fb1bbdb4da4Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a "Bio-Oxidizable" Prodrug Strategy: Design, Synthesis, and in Vitro Biological EvaluationPeauger, Ludovic; Azzouz, Rabah; Gembus, Vincent; Tintas, Mihaela-Liliana; Sopkova-de Oliveira Santos, Jana; Bohn, Pierre; Papamicael, Cyril; Levacher, VincentJournal of Medicinal Chemistry (2017), 60 (13), 5909-5926CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the std. drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compds. 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biol. expts.(d) Azzouz, R.; Peauger, L.; Gembus, V.; Ţînţaş, M. L.; Sopková-de Oliveira Santos, J.; Papamicaël, C.; Levacher, V. Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine ″bio-oxidizable″ prodrugs: Synthesis, biological evaluation and structure-activity relationship. Eur. J. Med. Chem. 2018, 145, 165– 190, DOI: 10.1016/j.ejmech.2017.12.084[Crossref], [PubMed], [CAS], Google Scholar198dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltlOrtg%253D%253D&md5=bd793423976324f61980466d8c0a4c68Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine "bio-oxidizable" prodrugs: Synthesis, biological evaluation and structure-activity relationshipAzzouz, Rabah; Peauger, Ludovic; Gembus, Vincent; Tintas, Mihaela-Liliana; Sopkova-de Oliveira Santos, Jana; Papamicael, Cyril; Levacher, VincentEuropean Journal of Medicinal Chemistry (2018), 145 (), 165-190CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A total of fifty one N-benzylpyridinium quaternary donepezil analogs B1-3 I [R = Ph, 2,3-dihydro-1,3-benzoxazol-2-yl, cyclohexyl, etc.; R1 = H, F, OH, OCH3; R2 = H, OCH3; R1, R2 = -OCH2O-; EWG = H, CN, CF3, C(O)NH2, etc.; X = Br, I; n = 0, 1, 2] and twenty two prodrugs A1-3 II was synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 >10 μM), a large no. of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addn., in silico docking studies were conducted for several compds. to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four sepd. isomers of prodrug II [R = 3-chlorophenyl; R1 = H, F, OH, OCH3; R2 = OCH3; EWG = C(O)NH2;n = 1] (IC50 ranging from 173 nM to 10 μM) but also significant variations of the oxidn. rate between two sepd. diastereoisomers of prodrug II [R = phenyl; R1 = R2 = OCH3; EWG = C(O)CH3; n = 2]. This work provides useful information in the search of a preclin. candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.
- 199Childress, E. S.; Alexopoulos, S. J.; Hoehn, K. L.; Santos, W. L. Small molecule mitochondrial uncouplers and their therapeutic potential. J. Med. Chem. 2018, 61, 4641– 4655, DOI: 10.1021/acs.jmedchem.7b01182[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVCks77F&md5=bef89f85633a157c8dadeaa0d0114403Small Molecule Mitochondrial Uncouplers and Their Therapeutic PotentialChildress, Elizabeth S.; Alexopoulos, Stephanie J.; Hoehn, Kyle L.; Santos, Webster L.Journal of Medicinal Chemistry (2018), 61 (11), 4641-4655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Small mol. mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metab. from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small mol. mitochondrial uncouplers reported to date and explore their potential as therapeutics.
- 200Millard, M.; Gallagher, J. D.; Olenyuk, B. Z.; Neamati, N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J. Med. Chem. 2013, 56, 9170– 9179, DOI: 10.1021/jm4012438[ACS Full Text], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1KktLvI&md5=433d093d02a482a570ea77e3b32629a3A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic CancersMillard, Melissa; Gallagher, John D.; Olenyuk, Bogdan Z.; Neamati, NouriJournal of Medicinal Chemistry (2013), 56 (22), 9170-9179CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, the authors describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium deriv. of the nitrogen mustard chlorambucil. The authors show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of re-purposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.
- 201(a) Ye, Y.; Zhang, T.; Yuan, H.; Li, D.; Lou, H.; Fan, P. Mitochondria-targeted lupane triterpenoid derivatives and their selective apoptosis-inducing anticancer mechanisms. J. Med. Chem. 2017, 60, 6353– 6363, DOI: 10.1021/acs.jmedchem.7b00679[ACS Full Text.], [CAS], Google Scholar201ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtV2qsr3E&md5=b1461bf97acb75e7c68e976462804065Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer MechanismsYe, Yaqing; Zhang, Tao; Yuan, Huiqing; Li, Defeng; Lou, Hongxiang; Fan, PeihongJournal of Medicinal Chemistry (2017), 60 (14), 6353-6363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Betulin and betulinic acid have been widely studied for their anticancer activities. However, their further development is limited due to low bioavailability, poor aq. soly., and limited intracellular accumulation. In the present study, a triphenylphosphonium cation moiety was linked to betulin and betulinic acid to specifically target them to cancer cell mitochondria. Biol. characterization established that uptake of mitochondria-targeted compd. 1a in the mitochondria of cancer cells was increased compared to betulin. The mitochondria-targeted derivs. of betulin and betulinic acid showed stronger cytotoxicity than their parent drugs and exhibited more cytotoxic effects in cancer cells than normal cells. The mechanisms may involve the mitochondrial apoptotic pathway, probably caused by the induction of reactive oxygen species prodn. and reducing mitochondrial membrane potential. More importantly, 1a significantly inhibited cancer cell proliferation and migration in an in vivo zebrafish xenograft model. Collectively, these results encourage further study of 1a analogs as anticancer agents.(b) Chang, W.; Liu, J.; Zhang, M.; Shi, H.; Zheng, S.; Jin, X.; Gao, Y.; Wang, S.; Ji, A.; Lou, H. Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation. Nat. Commun. 2018, 9, 5102, DOI: 10.1038/s41467-018-07633-9[Crossref], [PubMed], [CAS], Google Scholar201bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crns1aisQ%253D%253D&md5=430b9cf5f0a46c304c8e7b2e7afd089eEfflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cationChang Wenqiang; Liu Jun; Zhang Ming; Shi Hongzhuo; Zheng Sha; Jin Xueyang; Gao Yanhui; Wang Shuqi; Ji Aiguo; Lou HongxiangNature communications (2018), 9 (1), 5102 ISSN:.Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here we present a method for identification of PEPSs, and show that conjugation with mitochondria-targeting triphenylphosphonium cation (TPP(+)) can enhance or restore the compounds' antifungal activity. The screening method involves co-culturing a wild-type C. albicans strain and a Cdr efflux pump-deficient strain, labelled with different fluorescent proteins. We identify several PEPSs from a library of natural terpenes, and restore their antifungal activity against wild-type and azole-resistant C. albicans by conjugation with TPP(+). The most active conjugate (IS-2-Pi-TPP) kills C. albicans cells, prevents biofilm formation and eliminates preformed biofilms, without inducing significant resistance. The antifungal activity is accompanied by mitochondrial dysfunction and increased levels of intracellular reactive oxygen species. In addition, IS-2-Pi-TPP is effective against C. albicans in a mouse model of skin infection.
- 202Bauer, R. A. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discovery Today 2015, 20, 1061– 1073, DOI: 10.1016/j.drudis.2015.05.005[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlOnu7s%253D&md5=6ba5b016d2804c7d56838a2724b9a0b9Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapiesBauer, Renato A.Drug Discovery Today (2015), 20 (9), 1061-1073CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)Drugs that covalently bond to their biol. targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissoc. drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncol. and infectious disease.
- 203Zhao, Z.; Liu, Q.; Bliven, S.; Xie, L.; Bourne, P. E. Determining cysteines available for covalent inhibition across the human kinome. J. Med. Chem. 2017, 60, 2879– 2889, DOI: 10.1021/acs.jmedchem.6b01815[ACS Full Text], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVGjsLg%253D&md5=22ea95ce38eb0836d32c1332dba54fadDetermining Cysteines Available for Covalent Inhibition Across the Human KinomeZhao, Zheng; Liu, Qingsong; Bliven, Spencer; Xie, Lei; Bourne, Philip E.Journal of Medicinal Chemistry (2017), 60 (7), 2879-2889CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Covalently bound protein kinase inhibitors have been frequently designed to target non-catalytic Cys residues at the ATP binding site. Thus, it is important to know if a given Cys residue can form a covalent bond. Here, we combined a function-site interaction fingerprint method and DFT calcns. to det. the potential of Cys residues to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site Cys dataset was assembled. The orientation of the Cys SH group indicated which Cys residues could potentially form covalent bonds. These covalent inhibitor accessible Cys residues were located within 5 kinase regions (P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop and DFG-3 close to the DFG peptide). In an independent test set, these Cys residues covered 95% of covalent kinase inhibitors. Thus, this study provides new insights into Cys reactivity and preference which is important for the prospective development of covalent kinase inhibitors.
- 204Akbar, A.; McNeil, N. M. R.; Albert, M. R.; Ta, V.; Adhikary, G.; Bourgeois, K.; Eckert, R. L.; Keillor, J. W. Structure-activity relationships of potent, targeted covalent inhibitors that abolish both the transamidation and GTP binding activities of human tissue transglutaminase. J. Med. Chem. 2017, 60, 7910– 7927, DOI: 10.1021/acs.jmedchem.7b01070[ACS Full Text], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVejsrfL&md5=428ab48c5dd22fb85f14d0bdd21f7ab5Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue TransglutaminaseAkbar, Abdullah; McNeil, Nicole M. R.; Albert, Marie R.; Ta, Viviane; Adhikary, Gautam; Bourgeois, Karine; Eckert, Richard L.; Keillor, Jeffrey W.Journal of Medicinal Chemistry (2017), 60 (18), 7910-7927CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been assocd. with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, the authors present a series of targeted covalent inhibitors (TCIs) based on the previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (kinact/KI > 105 M-1 min-1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 μM, representing a significant improvement over the previously reported "hit" NC9.
- 205Muth, F.; El-Gokha, A.; Ansideri, F.; Eitel, M.; Doring, E.; Sievers-Engler, A.; Lange, A.; Boeckler, F. M.; Lammerhofer, M.; Koch, P.; Laufer, S. A. Tri- and tetrasubstituted pyridinylimidazoles as covalent inhibitors of c-Jun N-terminal kinase 3. J. Med. Chem. 2017, 60, 594– 607, DOI: 10.1021/acs.jmedchem.6b01180[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitV2nu7zI&md5=fbcdb576a6f2a2cbb30d35bcf7e9d062Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3Muth, Felix; El-Gokha, Ahmed; Ansideri, Francesco; Eitel, Michael; Doering, Eva; Sievers-Engler, Adrian; Lange, Andreas; Boeckler, Frank M.; Laemmerhofer, Michael; Koch, Pierre; Laufer, Stefan A.Journal of Medicinal Chemistry (2017), 60 (2), 594-607CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to the well validated pyridinylimidazole scaffolds varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the no. of off-targets. The most promising covalent inhibitor, 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide [2079881-38-0], inhibits the JNK3 in the sub-nanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes and displays excellent selectivity in a screen against 410 kinases. Covalent binding to Cys-154 of the enzyme was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.
- 206Shi, L.; Zhong, Z.; Li, X.; Zhou, Y.; Pan, Z. Discovery of an orally available janus kinase 3 selective covalent inhibitor. J. Med. Chem. 2019, 62, 1054, DOI: 10.1021/acs.jmedchem.8b01823[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjs1Ghug%253D%253D&md5=17792310c69501e5a645a63b79aa4826Discovery of an Orally Available Janus Kinase 3 Selective Covalent InhibitorShi, Liyang; Zhong, Zhenpeng; Li, Xitao; Zhou, Yiqing; Pan, ZhengyingJournal of Medicinal Chemistry (2019), 62 (2), 1054-1066CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3's strong binding preference to ATP (ATP), a no. of inhibitors exhibit large gaps between enzymic and cellular potency, which hampers efforts to dissect the roles of JAK3 in cellular settings. Using a targeted covalent inhibitor approach, we discovered compd. 32, which overcame ATP competition (1 mM) in the enzymic assay, and demonstrated significantly improved inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and human peripheral blood mononuclear cells. Compd. 32 also exhibited high selectivity within the JAK family and good pharmacokinetic properties. Thus, it may serve as a highly valuable tool mol. to study the overlapping roles of JAK family kinases in complex biol. settings. Our study also suggested that for covalent kinase inhibitors, esp. those targeting kinases with low Km ATP values, the reversible interactions between mols. and proteins should be carefully optimized to improve the overall potency.
- 207(a) Patricelli, M. P.; Janes, M. R.; Li, L. S.; Hansen, R.; Peters, U.; Kessler, L. V.; Chen, Y.; Kucharski, J. M.; Feng, J.; Ely, T.; Chen, J. H.; Firdaus, S. J.; Babbar, A.; Ren, P.; Liu, Y. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discovery 2016, 6, 316– 329, DOI: 10.1158/2159-8290.CD-15-1105[Crossref], [PubMed], [CAS], Google Scholar.207ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVyru7s%253D&md5=41db2f02006e8f0be7a9bb47354addcdSelective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive StatePatricelli, Matthew P.; Janes, Matthew R.; Li, Lian-Sheng; Hansen, Rasmus; Peters, Ulf; Kessler, Linda V.; Chen, Yuching; Kucharski, Jeff M.; Feng, Jun; Ely, Tess; Chen, Jeffrey H.; Firdaus, Sarah J.; Babbar, Anjali; Ren, Pingda; Liu, YiCancer Discovery (2016), 6 (3), 316-329CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)KRAS gain-of-function mutations occur in approx. 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRASG12C that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition obsd. for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRASG12C is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRASG12C mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. Significance: A cell-active, mutant-specific, covalent inhibitor of KRASG12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compd., we demonstrate that KRASG12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state.(b) Hansen, R.; Peters, U.; Babbar, A.; Chen, Y.; Feng, J.; Janes, M. R.; Li, L. S.; Ren, P.; Liu, Y.; Zarrinkar, P. P. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat. Struct. Mol. Biol. 2018, 25, 454, DOI: 10.1038/s41594-018-0061-5[Crossref], [PubMed], [CAS], Google Scholar207bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlKqu7nL&md5=b3f9198f55998306f3b881c256be22a9The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitorsHansen, Rasmus; Peters, Ulf; Babbar, Anjali; Chen, Yuching; Feng, Jun; Janes, Matthew R.; Li, Lian-Sheng; Ren, Pingda; Liu, Yi; Zarrinkar, Patrick P.Nature Structural & Molecular Biology (2018), 25 (6), 454-462CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small mols.; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biol. activity of these inhibitors has been described, the biochem. mechanism of how the compds. achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chem. reaction with Cys12 in human KRASG12C, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small mols. can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable.
- 208Brameld, K. A.; Owens, T. D.; Verner, E.; Venetsanakos, E.; Bradshaw, J. M.; Phan, V. T.; Tam, D.; Leung, K.; Shu, J.; LaStant, J.; Loughhead, D. G.; Ton, T.; Karr, D. E.; Gerritsen, M. E.; Goldstein, D. M.; Funk, J. O. Discovery of the irreversible covalent FGFR inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido [2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid tumors. J. Med. Chem. 2017, 60, 6516– 6527, DOI: 10.1021/acs.jmedchem.7b00360[ACS Full Text], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVykt7fK&md5=987069b645d5e0e36ccda5e5c81520b9Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid TumorsBrameld, Ken A.; Owens, Timothy D.; Verner, Erik; Venetsanakos, Eleni; Bradshaw, J. Michael; Phan, Vernon T.; Tam, Danny; Leung, Kwan; Shu, Jin; LaStant, Jacob; Loughhead, David G.; Ton, Tony; Karr, Dane E.; Gerritsen, Mary E.; Goldstein, David M.; Funk, Jens OliverJournal of Medicinal Chemistry (2017), 60 (15), 6516-6527CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clin. validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncol. indications. An irreversible covalent binding mechanism imparts many desirable pharmacol. benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chem. optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compd. 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.
- 209Wolle, P.; Hardick, J.; Cronin, S. J. F.; Engel, J.; Baumann, M.; Lategahn, J.; Penninger, J.; Rauh, D. Targeting the MKK7-JNK (Mitogen-Activated Protein Kinase Kinase 7-c Jun N-Terminal Kinase) pathway with covalent inhibitors. J. Med. Chem. 2019, 62, 2843, DOI: 10.1021/acs.jmedchem.9b00102[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFCqt70%253D&md5=9705c21d5e8df1b3b2f80e1125e66c74Targeting the MKK7-JNK (mitogen-activated protein kinase kinase 7-c-Jun N-terminal kinase) pathway with covalent inhibitorsWolle, Patrik; Hardick, Julia; Cronin, Shane J. F.; Engel, Julian; Baumann, Matthias; Lategahn, Jonas; Penninger, Josef M.; Rauh, DanielJournal of Medicinal Chemistry (2019), 62 (5), 2843-2848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffold.
- 210Lelais, G.; Epple, R.; Marsilje, T. H.; Long, Y. O.; McNeill, M.; Chen, B.; Lu, W.; Anumolu, J.; Badiger, S.; Bursulaya, B.; DiDonato, M.; Fong, R.; Juarez, J.; Li, J.; Manuia, M.; Mason, D. E.; Gordon, P.; Groessl, T.; Johnson, K.; Jia, Y.; Kasibhatla, S.; Li, C.; Isbell, J.; Spraggon, G.; Bender, S.; Michellys, P. Y. Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a novel, potent, and wt sparing covalent inhibitor of oncogenic (L858R, ex19del) and resistant (T790M) EGFR nutants for the treatment of EGFR mutant non-small-cell lung cancers. J. Med. Chem. 2016, 59, 6671– 6689, DOI: 10.1021/acs.jmedchem.5b01985[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOgu77P&md5=c106545d878ab3d675644b47099668a0Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung CancersLelais, Gerald; Epple, Robert; Marsilje, Thomas H.; Long, Yun O.; McNeill, Matthew; Chen, Bei; Lu, Wenshuo; Anumolu, Jaganmohan; Badiger, Sangamesh; Bursulaya, Badry; DiDonato, Michael; Fong, Rina; Juarez, Jose; Li, Jie; Manuia, Mari; Mason, Daniel E.; Gordon, Perry; Groessl, Todd; Johnson, Kevin; Jia, Yong; Kasibhatla, Shailaja; Li, Chun; Isbell, John; Spraggon, Glen; Bender, Steven; Michellys, Pierre-YvesJournal of Medicinal Chemistry (2016), 59 (14), 6671-6689CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through mol. docking studies we converted a mutant-selective high-throughput screening hit (7) into a no. of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compds. with good tolerability and efficacy that ultimately led to the selection of 47 as the clin. candidate.
- 211Horton, J. R.; Woodcock, C. B.; Chen, Q.; Liu, X.; Zhang, X.; Shanks, J.; Rai, G.; Mott, B. T.; Jansen, D. J.; Kales, S. C.; Henderson, M. J.; Cyr, M.; Pohida, K.; Hu, X.; Shah, P.; Xu, X.; Jadhav, A.; Maloney, D. J.; Hall, M. D.; Simeonov, A.; Fu, H.; Vertino, P. M.; Cheng, X. Structure-based engineering of irreversible inhibitors against histone lysine demethylase KDM5A. J. Med. Chem. 2018, 61, 10588, DOI: 10.1021/acs.jmedchem.8b01219[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2rur3P&md5=5ab97cae54ccff28f65071fa41a70c0aStructure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5AHorton, John R.; Woodcock, Clayton B.; Chen, Qin; Liu, Xu; Zhang, Xing; Shanks, John; Rai, Ganesha; Mott, Bryan T.; Jansen, Daniel J.; Kales, Stephen C.; Henderson, Mark J.; Cyr, Matthew; Pohida, Katherine; Hu, Xin; Shah, Pranav; Xu, Xin; Jadhav, Ajit; Maloney, David J.; Hall, Matthew D.; Simeonov, Anton; Fu, Haian; Vertino, Paula M.; Cheng, XiaodongJournal of Medicinal Chemistry (2018), 61 (23), 10588-10601CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a deriv. contg. a ((dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and detd. the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concn. and persisted even after dialysis, consistent with covalent modification.
- 212Liu, Y.; Xie, Z.; Zhao, D.; Zhu, J.; Mao, F.; Tang, S.; Xu, H.; Luo, C.; Geng, M.; Huang, M.; Li, J. Development of the first generation of disulfide-based subtype-selective and potent covalent pyruvate dehydrogenase kinase 1 (PDK1) inhibitors. J. Med. Chem. 2017, 60, 2227– 2244, DOI: 10.1021/acs.jmedchem.6b01245[ACS Full Text], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtlyjtr0%253D&md5=7529ce2fc9d1a138a8d1405a23f7e4e8Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) InhibitorsLiu, Yifu; Xie, Zuoquan; Zhao, Dan; Zhu, Jin; Mao, Fei; Tang, Shuai; Xu, Hui; Luo, Cheng; Geng, Meiyu; Huang, Min; Li, JianJournal of Medicinal Chemistry (2017), 60 (6), 2227-2244CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metab. The authors previously described Bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, based on the scaffold of JX06, the authors identify two novel types of disulfide-based PDK1 inhibitors. The most potent analog, bis(1,4-oxazepan-4-yl-thiocarbonyl)disulfide (3a), effectively inhibits PDK1 both at the mol. (kinact/Ki = 4.17 × 103 M-1s-1) and the cellular level (down to 0.1 μM). In contrast to JX06, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. Compd. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no neg. effect to the mice wt. Collectively, these data demonstrate that 3a may be an excellent lead compd. for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.
- 213(a) McAllister, L. A.; O’Neil, S. V.; Fonseca, K. R.; Piro, J. R.; Cianfrogna, J. A.; Foley, T. L.; Gilbert, A. M.; Harris, A. R.; Helal, C. J.; Johnson, D. S.; Montgomery, J. I.; Nason, D. M.; Noell, S.; Pandit, J.; Rogers, B. N.; Samad, T. A.; Shaffer, C. L.; da Silva, R. G.; Uccello, D. P.; Webb, D.; Brodney, M. A. Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation. J. Med. Chem. 2018, 61, 3008– 3026, DOI: 10.1021/acs.jmedchem.8b00070[ACS Full Text.], [CAS], Google Scholar213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjslKlurw%253D&md5=984babc4de306b698756e9c2a9fc5c8eDiscovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of NeuroinflammationMcAllister, Laura A.; Butler, Christopher R.; Mente, Scot; O'Neil, Steven V.; Fonseca, Kari R.; Piro, Justin R.; Cianfrogna, Julie A.; Foley, Timothy L.; Gilbert, Adam M.; Harris, Anthony R.; Helal, Christopher J.; Johnson, Douglas S.; Montgomery, Justin I.; Nason, Deane M.; Noell, Stephen; Pandit, Jayvardhan; Rogers, Bruce N.; Samad, Tarek A.; Shaffer, Christopher L.; da Silva, Rafael G.; Uccello, Daniel P.; Webb, Damien; Brodney, Michael A.Journal of Medicinal Chemistry (2018), 61 (7), 3008-3026CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compd. I (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochem. property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving soly., and minimizing chem. lability. Compd. I achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.(b) Butler, C. R.; Beck, E. M.; Harris, A.; Huang, Z.; McAllister, L. A.; Am Ende, C. W.; Fennell, K.; Foley, T. L.; Fonseca, K.; Hawrylik, S. J.; Johnson, D. S.; Knafels, J. D.; Mente, S.; Noell, G. S.; Pandit, J.; Phillips, T. B.; Piro, J. R.; Rogers, B. N.; Samad, T. A.; Wang, J.; Wan, S.; Brodney, M. A. Azetidine and piperidine carbamates as efficient, covalent inhibitors of monoacylglycerol lipase. J. Med. Chem. 2017, 60, 9860– 9873, DOI: 10.1021/acs.jmedchem.7b01531[ACS Full Text], [CAS], Google Scholar213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWqurzO&md5=b89f7d44f611dd84cd49a8d240ac26b0Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol LipaseButler, Christopher R.; Beck, Elizabeth M.; Harris, Anthony; Huang, Zhen; McAllister, Laura A.; am Ende, Christopher W.; Fennell, Kimberly; Foley, Timothy L.; Fonseca, Kari; Hawrylik, Steven J.; Johnson, Douglas S.; Knafels, John D.; Mente, Scot; Noell, G. Stephen; Pandit, Jayvardhan; Phillips, Tracy B.; Piro, Justin R.; Rogers, Bruce N.; Samad, Tarek A.; Wang, Jane; Wan, Shuangyi; Brodney, Michael A.Journal of Medicinal Chemistry (2017), 60 (23), 9860-9873CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degrdn. of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein the authors describe highly efficient MAGL inhibitors, identified through a parallel medicinal chem. approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compd. 6 (1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-phenyl-1H-pyrazol-3-yl)azetidine-1-carboxylate), a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
- 214Kulkarni, P. M.; Kulkarni, A. R.; Korde, A.; Tichkule, R. B.; Laprairie, R. B.; Denovan-Wright, E. M.; Zhou, H.; Janero, D. R.; Zvonok, N.; Makriyannis, A.; Cascio, M. G.; Pertwee, R. G.; Thakur, G. A. Novel electrophilic and photoaffinity covalent probes for mapping the cannabinoid 1 receptor allosteric site(s). J. Med. Chem. 2016, 59, 44– 60, DOI: 10.1021/acs.jmedchem.5b01303[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKlsbvN&md5=bdd1f5e67ef28ecf57773817c7c2c00fNovel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)Kulkarni, Pushkar M.; Kulkarni, Abhijit R.; Korde, Anisha; Tichkule, Ritesh B.; Laprairie, Robert B.; Denovan-Wright, Eileen M.; Zhou, Han; Janero, David R.; Zvonok, Nikolai; Makriyannis, Alexandros; Cascio, Maria G.; Pertwee, Roger G.; Thakur, Ganesh A.Journal of Medicinal Chemistry (2016), 59 (1), 44-60CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Undesirable side effects assocd. with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R neg. allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochem. characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust pos. allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs.
- 215Doornbos, M. L. J.; Wang, X.; Vermond, S. C.; Peeters, L.; Pérez-Benito, L.; Trabanco, A. A.; Lavreysen, H.; Cid, J. M.; Heitman, L. H.; Tresadern, G.; IJzerman, A. P. Covalent allosteric probe for the metabotropic glutamate receptor 2: Design, synthesis, and pharmacological characterization. J. Med. Chem. 2019, 62, 223, DOI: 10.1021/acs.jmedchem.8b00051[ACS Full Text], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Cgs78%253D&md5=5d4cafa60439bbcdb81667789326099aCovalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological CharacterizationDoornbos, Maarten L. J.; Wang, Xuesong; Vermond, Sophie C.; Peeters, Luc; Perez-Benito, Laura; Trabanco, Andres A.; Lavreysen, Hilde; Cid, Jose Maria; Heitman, Laura H.; Tresadern, Gary; IJzerman, Adriaan P.Journal of Medicinal Chemistry (2019), 62 (1), 223-233CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Covalent labeling of G protein-coupled receptors (GPCRs) by small mols. is a powerful approach to understand binding modes, mechanism of action, pharmacol., and even facilitate structure elucidation. We report the first covalent pos. allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacol. characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compd. in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chem. biol. approaches.
- 216Casimiro-Garcia, A.; Trujillo, J. I.; Vajdos, F.; Juba, B.; Banker, M. E.; Aulabaugh, A.; Balbo, P.; Bauman, J.; Chrencik, J.; Coe, J. W.; Czerwinski, R.; Dowty, M.; Knafels, J. D.; Kwon, S.; Leung, L.; Liang, S.; Robinson, R. P.; Telliez, J. B.; Unwalla, R.; Yang, X.; Thorarensen, A. Identification of cyanamide-based Janus kinase 3 (JAK3) covalent inhibitors. J. Med. Chem. 2018, 61, 10665, DOI: 10.1021/acs.jmedchem.8b01308[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitF2qtrjK&md5=12832ed66b8fc89d5f6ef9a3aa4ea20fIdentification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent InhibitorsCasimiro-Garcia, Agustin; Trujillo, John I.; Vajdos, Felix; Juba, Brian; Banker, Mary Ellen; Aulabaugh, Ann; Balbo, Paul; Bauman, Jonathan; Chrencik, Jill; Coe, Jotham W.; Czerwinski, Robert; Dowty, Martin; Knafels, John D.; Kwon, Soojin; Leung, Louis; Liang, Sidney; Robinson, Ralph P.; Telliez, Jean-Baptiste; Unwalla, Ray; Yang, Xin; Thorarensen, AtliJournal of Medicinal Chemistry (2018), 61 (23), 10665-10699CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallog., kinetic, and computational studies, interaction of cyanamide I with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by II. In relevant cell-based assays and in agreement with previous results from this group, II demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for I. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
- 217Chan, A. H.; Lee, W. G.; Spasov, K. A.; Cisneros, J. A.; Kudalkar, S. N.; Petrova, Z. O.; Buckingham, A. B.; Anderson, K. S.; Jorgensen, W. Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: from design to protein crystallography. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 9725– 9730, DOI: 10.1073/pnas.1711463114[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlOhtbnM&md5=e3adcd94ed487e866026a3d46f4e09d8Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallographyChan, Albert H.; Lee, Won-Gil; Spasov, Krasimir A.; Cisneros, Jose A.; Kudalkar, Shalley N.; Petrova, Zaritza O.; Buckingham, Amanda B.; Anderson, Karen S.; Jorgensen, William L.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (36), 9725-9730CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance assocd. with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, esp. in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallog., and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.
- 218Shindo, N.; Fuchida, H.; Sato, M.; Watari, K.; Shibata, T.; Kuwata, K.; Miura, C.; Okamoto, K.; Hatsuyama, Y.; Tokunaga, K.; Sakamoto, S.; Morimoto, S.; Abe, Y.; Shiroishi, M.; Caaveiro, J. M. M.; Ueda, T.; Tamura, T.; Matsunaga, N.; Nakao, T.; Koyanagi, S.; Ohdo, S.; Yamaguchi, Y.; Hamachi, I.; Ono, M.; Ojida, A. Selective and reversible modification of kinase cysteines with chlorofluoroacetamides. Nat. Chem. Biol. 2019, 15, 250, DOI: 10.1038/s41589-018-0204-3[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlvFSgur4%253D&md5=f6c8886d540ea26a8abecd950feba913Selective and reversible modification of kinase cysteines with chlorofluoroacetamidesShindo, Naoya; Fuchida, Hirokazu; Sato, Mami; Watari, Kosuke; Shibata, Tomohiro; Kuwata, Keiko; Miura, Chizuru; Okamoto, Kei; Hatsuyama, Yuji; Tokunaga, Keisuke; Sakamoto, Seiichi; Morimoto, Satoshi; Abe, Yoshito; Shiroishi, Mitsunori; Caaveiro, Jose M. M.; Ueda, Tadashi; Tamura, Tomonori; Matsunaga, Naoya; Nakao, Takaharu; Koyanagi, Satoru; Ohdo, Shigehiro; Yamaguchi, Yasuchika; Hamachi, Itaru; Ono, Mayumi; Ojida, AkioNature Chemical Biology (2019), 15 (3), 250-258CODEN: NCBABT; ISSN:1552-4450. (Nature Research)Irreversible inhibition of disease-assocd. proteins with small mols. is a powerful approach for achieving increased and sustained pharmacol. potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concn. range (0.1-10 μM). The cysteine adduct of the CFA deriv. was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline, (2R)-1-(2-chloro-2-fluoroacetyl)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)-propoxy]quinazolin-6-yl]pyrrolidine-2-carboxamide [2226257-92-5] (NS-062, compd. 51) significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.
- 219(a) Brouwer, A. J.; Jonker, A.; Werkhoven, P.; Kuo, E.; Li, N.; Gallastegui, N.; Kemmink, J.; Florea, B. I.; Groll, M.; Overkleeft, H. S.; Liskamp, R. M. Peptido sulfonyl fluorides as new powerful proteasome inhibitors. J. Med. Chem. 2012, 55, 10995– 1003, DOI: 10.1021/jm301443r[ACS Full Text.], [CAS], Google Scholar219ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslalurjE&md5=e84873c90746c6642013c03b51b40bcfPeptido sulfonyl fluorides as new powerful proteasome inhibitorsBrouwer, Arwin J.; Jonker, Anika; Werkhoven, Paul; Kuo, Ethan; Li, Nan; Gallastegui, Nerea; Kemmink, Johan; Florea, Bogdan I.; Groll, Michael; Overkleeft, Herman S.; Liskamp, Rob M. J.Journal of Medicinal Chemistry (2012), 55 (24), 10995-11003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu3-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC50 of 7 nM. A no. of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the β5 proteasome subunit.(b) Artschwager, R.; Ward, D.; Gannon, S.; Brouwer, A. J.; van de Langemheen, H.; Kowalski, H.; Liskamp, R. Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides. J. Med. Chem. 2018, 61, 5395– 5411, DOI: 10.1021/acs.jmedchem.8b00685[ACS Full Text], [CAS], Google Scholar219bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVGktrc%253D&md5=eb1a22968da0b5b4622e4f9b65af7326Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl FluoridesArtschwager, Raik; Ward, David J.; Gannon, Susan; Brouwer, Arwin J.; van de Langemheen, Helmus; Kowalski, Hubert; Liskamp, Rob M. J.Journal of Medicinal Chemistry (2018), 61 (12), 5395-5411CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A unique category of basic side chain contg. amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivs. as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compds. are slightly more selective for inhibition of the constitutive over the immunoproteasome.
- 220Yang, F.; Zhu, M.; Zhang, J.; Zhou, H. Synthesis of biologically active boron-containing compounds. MedChemComm 2018, 9, 201– 211, DOI: 10.1039/C7MD00552K[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVOrt7jN&md5=11018b19779619600cdb63d60ae07407Synthesis of biologically active boron-containing compoundsYang, Fei; Zhu, Mingyan; Zhang, Jinyi; Zhou, HuchenMedChemComm (2018), 9 (2), 201-211CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Boron-contg. compds. which possess unique and attractive properties have received increasing attention from the pharmaceutical industry and academia recently. They have shown interesting and useful biol. activities, including antibacterial, antifungal, antiparasitic, antiviral, and anti-inflammatory activities. In this review, the synthetic strategies for various boron-contg. compds., including peptidyl boronic acids, benzoxaboroles, benzoxaborines, benzodiazaborines, amine carboxyboranes, and amine cyanoboranes are summarized. Representative structures of each structural class and recently developed biol. active boron-contg. compds. are used as examples in this review.
- 221(a) Smith, T. P.; Windsor, I. W.; Forest, K. T.; Raines, R. T. Stilbene boronic acids form a covalent bond with human transthyretin and inhibit its aggregation. J. Med. Chem. 2017, 60, 7820– 7834, DOI: 10.1021/acs.jmedchem.7b00952[ACS Full Text.], [CAS], Google Scholar221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2lur%252FN&md5=63d28cf990198b6e0dce953af76fb752Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its AggregationSmith, Thomas P.; Windsor, Ian W.; Forest, Katrina T.; Raines, Ronald T.Journal of Medicinal Chemistry (2017), 60 (18), 7820-7834CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Transthyretin (TTR) is a homotetrameric protein. Its dissocn. into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small mols. to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallog. anal. of nine TTR·ligand complexes. The ensuing structure-function data led to a sym. diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-mol. drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.(b) Windsor, I. W.; Palte, M. J.; Lukesh, J. C., 3rd.; Gold, B.; Forest, K. T.; Raines, R. T. Sub-picomolar inhibition of hiv-1 protease with a boronic acid. J. Am. Chem. Soc. 2018, 140, 14015– 14018, DOI: 10.1021/jacs.8b07366[ACS Full Text], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFaltbnI&md5=ad7d7a58f8e3cad8c6fea7cb2823741cSub-picomolar Inhibition of HIV-1 Protease with a Boronic AcidWindsor, Ian W.; Palte, Michael J.; Lukesh, John C.; Gold, Brian; Forest, Katrina T.; Raines, Ronald T.Journal of the American Chemical Society (2018), 140 (43), 14015-14018CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallog. demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short (rO···O = 2.2 Å), and d. functional theory anal. reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-mol. ligands.
- 222Nitsche, C.; Zhang, L.; Weigel, L. F.; Schilz, J.; Graf, D.; Bartenschlager, R.; Hilgenfeld, R.; Klein, C. D. Peptide-boronic acid inhibitors of flaviviral proteases: medicinal chemistry and structural biology. J. Med. Chem. 2017, 60, 511– 516, DOI: 10.1021/acs.jmedchem.6b01021[ACS Full Text], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFGrtLvE&md5=a9671140deb2c9014ae8e1429cb5074fPeptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural BiologyNitsche, Christoph; Zhang, Linlin; Weigel, Lena F.; Schilz, Jonas; Graf, Dominik; Bartenschlager, Ralf; Hilgenfeld, Rolf; Klein, Christian D.Journal of Medicinal Chemistry (2017), 60 (1), 511-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile and dengue virus proteases. The resulting compds. have Ki values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure-activity relationships and a high resoln. x-ray co-crystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens.
- 223Zervosen, A.; Herman, R.; Kerff, F.; Herman, A.; Bouillez, A.; Prati, F.; Pratt, R. F.; Frère, J. M.; Joris, B.; Luxen, A.; Charlier, P.; Sauvage, E. Unexpected tricovalent binding mode of boronic acids within the active site of a penicillin-binding protein. J. Am. Chem. Soc. 2011, 133, 10839– 10848, DOI: 10.1021/ja200696y[ACS Full Text], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvFKhsr0%253D&md5=847cbfcb9458d610240b34d01a99a261Unexpected Tricovalent Binding Mode of Boronic Acids within the Active Site of a Penicillin-Binding ProteinZervosen, Astrid; Herman, Raphael; Kerff, Frederic; Herman, Alexandre; Bouillez, Andre; Prati, Fabio; Pratt, R. F.; Frere, Jean-Marie; Joris, Bernard; Luxen, Andre; Charlier, Paulette; Sauvage, EricJournal of the American Chemical Society (2011), 133 (28), 10839-10848CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Boronic acids bearing appropriate side chains are good inhibitors of serine amidohydrolases. The boron usually adopts a tetrahedral conformation, bound to the nucleophilic serine of the active site and mimicking the transition state of the enzymic reaction. We have solved the structures of complexes of a penicillin-binding protein (PBP), the DD-peptidase from Actinomadura sp. R39, with four amidomethylboronic acids (2,6-dimethoxybenzamidomethylboronic acid, phenylacetamidomethylboronic acid, 2-chlorobenzamidomethylboronic acid, and 2-nitrobenzamidomethylboronic acid) and the pinacol ester derived from phenylacetamidomethylboronic acid. We found that in each case, the boron forms a tricovalent adduct with the Oγ from Ser49 and Ser298, and the terminal amine group of Lys410, three key residues involved in the catalytic mechanism of penicillin-binding proteins. This represents the first tricovalent enzyme-inhibitor adducts obsd. by crystallog. In two of the five R39-boronate structures, the boronic acid is found as a tricovalent adduct in two monomers of the asym. unit and as a monocovalent adduct with the active serine in the two remaining monomers of the asym. unit. Formation of the tricovalent complex from a classical monocovalent complex may involve rotation around the Ser49 Cα-Cβ bond to place the boron in a position to interact with Ser298 and Lys410, and a twisting of the side-chain amide such that its carbonyl oxygen is able to hydrogen bond to the oxyanion hole NH of Thr413. Biphasic kinetics were obsd. in three of the five cases, and details of the reaction between R39 and 2,6-dimethoxybenzamidomethylboronic acid were studied. Observation of biphasic kinetics was not, however, thought to be correlated with formation of tricovalent complexes, assuming that the latter do form in soln. On the basis of the crystallog. and kinetic results, a reaction scheme for this unexpected inhibition by boronic acids is proposed.
- 224(a) Powers, R. A.; Swanson, H. C.; Taracila, M. A.; Florek, N. W.; Romagnoli, C.; Caselli, E.; Prati, F.; Bonomo, R. A.; Wallar, B. J. Biochemical and structural analysis of inhibitors targeting the ADC-7 cephalosporinase of Acinetobacter baumannii. Biochemistry 2014, 53, 7670– 7679, DOI: 10.1021/bi500887n[ACS Full Text.], [CAS], Google Scholar224ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyrtLnJ&md5=9b36ea9ec80e8f17308f9c1e0e2f6298Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumanniiPowers, Rachel A.; Swanson, Hollister C.; Taracila, Magdalena A.; Florek, Nicholas W.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Bonomo, Robert A.; Wallar, Bradley J.Biochemistry (2014), 53 (48), 7670-7679CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)β-Lactam resistance in Acinetobacter baumannii presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C β-lactamase enzymes, known as Acinetobacter-derived cephalosporinases (ADCs). Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two boronic acid transition state inhibitors (BATSIs S02030 and SM23) that are chem. distinct from β-lactams were designed and tested for inhibition of ADC enzymes. BATSIs SM23 and S02030 bind with high affinity to ADC-7, a chromosomal cephalosporinase from Acinetobacter baumannii (Ki = 21.1 ± 1.9 nM and 44.5 ± 2.2 nM, resp.). The X-ray crystal structures of ADC-7 were detd. in both the apo form (1.73 Å resoln.) and in complex with S02030 (2.0 Å resoln.). In the complex, S02030 makes several canonical interactions: the O1 oxygen of S02030 is bound in the oxyanion hole, and the R1 amide group makes key interactions with conserved residues Asn152 and Gln120. In addn., the carboxylate group of the inhibitor is meant to mimic the C3/C4 carboxylate found in β-lactams. The C3/C4 carboxylate recognition site in class C enzymes is comprised of Asn346 and Arg349 (AmpC numbering), and these residues are conserved in ADC-7. Interestingly, in the ADC-7/S02030 complex, the inhibitor carboxylate group is obsd. to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme AmpC. A thermodn. anal. suggests that ΔH driven compds. may be optimized to generate new lead agents. The ADC-7/BATSI complex provides insight into recognition of non-β-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel β-lactamase inhibitors against a key resistance target.(b) Caselli, E.; Romagnoli, C.; Vahabi, R.; Taracila, M. A.; Bonomo, R. A.; Prati, F. Click chemistry in lead optimization of boronic acids as β-lactamase inhibitors. J. Med. Chem. 2015, 58, 5445– 5458, DOI: 10.1021/acs.jmedchem.5b00341[ACS Full Text.], [CAS], Google Scholar224bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKit7nM&md5=b2499e36d43734a1ea8b706b73e454feClick Chemistry in Lead Optimization of Boronic Acids as β-Lactamase InhibitorsCaselli, Emilia; Romagnoli, Chiara; Vahabi, Roza; Taracila, Magdalena A.; Bonomo, Robert A.; Prati, FabioJournal of Medicinal Chemistry (2015), 58 (14), 5445-5458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Boronic acid transition-state inhibitors (BATSIs) represent one of the most promising classes of β-lactamase inhibitors. Here the authors describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic acids, which were synthesized by combining the asym. homologation of boronates with Cu-catalyzed azide-alkyne cycloaddn. for the stereoselective insertion of the amido group and the regioselective formation of the 1,4-disubstituted triazole, resp. This synthetic pathway, which avoids intermediate purifications, proved to be flexible and efficient, affording in good yields a panel of 14 BATSIs bearing three different R1 amide side chains (acetamido, benzylamido, and 2-thienylacetamido) and several R substituents on the triazole. This small library was tested against two clin. relevant class C β-lactamases from Enterobacter spp. and Pseudomonas aeruginosa. The Ki value of the best compd. (13a) was ≥4 nM with significant redn. of bacterial resistance to the combination of cefotaxime/13a.(c) Bouza, A. A.; Swanson, H. C.; Smolen, K. A.; VanDine, A. L.; Taracila, M. A.; Romagnoli, C.; Caselli, E.; Prati, F.; Bonomo, R. A.; Powers, R. A.; Wallar, B. J. Structure-based analysis of boronic acids as inhibitors of acinetobacter-derived cephalosporinase-7, a unique class C β-lactamase. ACS Infect. Dis. 2018, 4, 325– 336, DOI: 10.1021/acsinfecdis.7b00152[ACS Full Text.], [CAS], Google Scholar224chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWntrfF&md5=6453dfb5439845b40e5a9085470cf5ffStructure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-LactamaseBouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; VanDine, Alison L.; Taracila, Magdalena A.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Bonomo, Robert A.; Powers, Rachel A.; Wallar, Bradley J.ACS Infectious Diseases (2018), 4 (3), 325-336CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12,000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is a result of class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clin. used β-lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. Ki values ranged from low micromolar to sub-nanomolar, and CD (CD) demonstrated that each inhibitor stabilizes the β-lactamase-inhibitor complexes. Addnl., X-ray crystal structures of ADC-7 in complex with five inhibitors were detd. (resolns. from 1.80-2.09 Å). In the ADC-7/CR192 complex, the BATSI with the lowest Ki (0.45 nM) and greatest ΔTm (+9 °C), a trifluoromethyl substituent interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. The ADC-7/BATSI complexes detd. in this study shed light into the unique recognition sites in ADC enzymes, and also offer insight into further structure-based optimization of these inhibitors.(d) Caselli, E.; Romagnoli, C.; Powers, R. A.; Taracila, M. A.; Bouza, A. A.; Swanson, H. C.; Smolen, K. A.; Fini, F.; Wallar, B. J.; Bonomo, R. A.; Prati, F. Inhibition of acinetobacter-derived cephalosporinase: exploring the carboxylate recognition site using novel β-lactamase inhibitors. ACS Infect. Dis. 2018, 4, 337– 348, DOI: 10.1021/acsinfecdis.7b00153[ACS Full Text], [CAS], Google Scholar224dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWnt7nE&md5=d3f02a44ba426f305b6c43ea8f4b78fcInhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase InhibitorsCaselli, Emilia; Romagnoli, Chiara; Powers, Rachel A.; Taracila, Magdalena A.; Bouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; Fini, Francesco; Wallar, Bradley J.; Bonomo, Robert A.; Prati, FabioACS Infectious Diseases (2018), 4 (3), 337-348CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular compd. S02030 (Ki = 44 nM) proved to be a good lead compd. against ADC-7 (Acinetobacter Derived Cephalosporinase), one of the most significant resistance determinants in A. baumannii. The at. structure of the ADC-7/S02030 complex highlighted the importance of crit. structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in β-lactams, we designed, synthesized, and characterized six derivs. of S02030 (3a). Out of the six compds., the best inhibitors proved to be those with an explicit neg. charge (compds. 3a-c and 3h,j, Ki = 44-115 nM), which is in contrast to the derivs. where the neg. charge is omitted, such as the amide deriv. 3d (Ki = 224 nM) and the hydroxyamide deriv. 3e (Ki = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compds. 3c, SM23, and EC04 were detd. All three compds. share the same structural features as in S02030, but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the neg. charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than binding site in ADC enzymes. Furthermore, this class of compds. was tested against resistant clin. strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.
- 225Mons, E.; Jansen, I. D. C.; Loboda, J.; van Doodewaerd, B. R.; Hermans, J.; Verdoes, M.; van Boeckel, C. A. A.; van Veelen, P. A.; Turk, B.; Turk, D.; Ovaa, H. The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K. J. Am. Chem. Soc. 2019, 141, 3507, DOI: 10.1021/jacs.8b11027[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKjtbY%253D&md5=3a18718aa722a8d46c5be1cf07dd077bThe Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin KMons, Elma; Jansen, Ineke D. C.; Loboda, Jure; van Doodewaerd, Bjorn R.; Hermans, Jill; Verdoes, Martijn; van Boeckel, Constant A. A.; van Veelen, Peter A.; Turk, Boris; Turk, Dusan; Ovaa, HuibJournal of the American Chemical Society (2019), 141 (8), 3507-3514CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small mol. inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure anal. The rate of covalent bond formation (kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small mol. inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.
- 226Palermo, G.; Branduardi, D.; Masetti, M.; Lodola, A.; Mor, M.; Piomelli, D.; Cavalli, A.; De Vivo, M. Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas. J. Med. Chem. 2011, 54, 6612– 6623, DOI: 10.1021/jm2004283[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFCgsb3O&md5=3130e9ef929a52cc0900ad77b38a7453Covalent Inhibitors of Fatty Acid Amide Hydrolase: A Rationale for the Activity of Piperidine and Piperazine Aryl UreasPalermo, Giulia; Branduardi, Davide; Masetti, Matteo; Lodola, Alessio; Mor, Marco; Piomelli, Daniele; Cavalli, Andrea; De Vivo, MarcoJournal of Medicinal Chemistry (2011), 54 (19), 6612-6623CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and potent FAAH inhibitors (FAAHi), there are the cyclic piperidine and piperazine aryl ureas. FAAH hydrolyzes efficiently the amide bond of these compds., forming a covalent enzyme-inhibitor adduct. To rationalize this exptl. evidence, we performed an extensive computational anal. centered on piperidine-based PF750 (1) and piperazine-based JNJ1661010 (2), two potent lead compds. used to generate covalent inhibitors as clin. candidates. We found that FAAH induces a distortion of the amide bond of the piperidine and piperazine aryl ureas. Quantum mechanics/mol. mechanics ΔELUMO-HOMO energies indicate that the obsd. enzyme-induced distortion of the amide bond favors the formation of a covalent FAAH-inhibitor adduct. These findings could help in the rational structure-based design of novel covalent FAAHi.
- 227Chatterjee, P.; Botello-Smith, W. M.; Zhang, H.; Qian, L.; Alsamarah, A.; Kent, D.; Lacroix, J. J.; Baudry, M.; Luo, Y. Can relative binding free energy predict selectivity of reversible covalent inhibitors?. J. Am. Chem. Soc. 2017, 139, 17945– 17952, DOI: 10.1021/jacs.7b08938[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslyrs7bI&md5=e6a38ff570134e956eb43bd4a874ca55Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?Chatterjee, Payal; Botello-Smith, Wesley M.; Zhang, Han; Qian, Li; Alsamarah, Abdelaziz; Kent, David; Lacroix, Jerome J.; Baudry, Michel; Luo, YunJournal of the American Chemical Society (2017), 139 (49), 17945-17952CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Reversible covalent inhibitors have many clin. advantages over noncovalent or irreversible covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, the authors lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model. To prove the concept, the authors employed free energy perturbation (FEP) coupled with λ-exchange mol. dynamics method to calc. the binding free energy of a series of α-ketoamide analogs relative to a common warhead scaffold, in both noncovalent and covalent binding states, and for two highly homologous proteases, calpain-1 and calpain-2. The authors conclude that covalent binding state alone, in general, can be used to predict reversible covalent binding selectivity. However, exceptions may exist. Therefore, the authors also discuss the conditions under which the noncovalent binding step is no longer negligible and propose to combine the relative FEP calcns. with a single QM/MM calcn. of warhead to predict the binding affinity and binding kinetics. The FEP calcns. also revealed that covalent and noncovalent binding states of an inhibitor do not necessarily exhibit the same selectivity. Thus, investigating both binding states, as well as the kinetics will provide extremely useful information for optimizing reversible covalent inhibitors.
- 228Scarpino, A.; Ferenczy, G. G.; Keseru, G. M. Comparative evaluation of covalent docking tools. J. Chem. Inf. Model. 2018, 58, 1441– 1458, DOI: 10.1021/acs.jcim.8b00228[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSmsLzE&md5=d74695be1f047ac840527161c510692dComparative Evaluation of Covalent Docking ToolsScarpino, Andrea; Ferenczy, Gyorgy G.; Keseru, Gyorgy M.Journal of Chemical Information and Modeling (2018), 58 (7), 1441-1458CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity of covalent inhibitors. Here we compare the performance of six covalent docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE, for reproducing exptl. binding modes in an unprecedently large and diverse set of covalent complexes. It was found that 40-60% of the top scoring ligand poses are within 2.0 Å RMSD from the exptl. binding mode. This rate showed program dependent increase and achieved 50-90% when the best RMSD among the top ten scoring poses was considered. This performance is comparable to that of noncovalent docking tools and therefore suggests that anchoring the ligand does not necessarily improve the accuracy of the prediction. The effect of various ligand and protein features on the docking performance was investigated. At the level of warhead chem., higher success rate was found for Michael addns., nucleophilic addns. and nucleophilic substitutions than for ring opening reactions and disulfide formation. Increasing ligand size and flexibility generally affects pose predictions unfavorably, although AutoDock4, FITTED, and ICM-Pro were found to be less sensitive up to 35 heavy atoms. Increasing the accessibility of the target cysteine tends to result in improved binding mode predictions. Docking programs show protein dependent performance suggesting a target-dependent choice of the optimal docking tool. It was found that noncovalent docking into Cys/Ala mutated proteins by ICM-Pro and Glide reproduced exptl. binding modes with only slightly lower performance and at a significantly lower computational expense than covalent docking did. Overall, our results highlight the key factors influencing the docking performance of the investigated tools and they give guidelines for selecting the optimal combination of warheads, ligands, and tools for the system investigated. Results also identify the most important aspects to be considered for developing improved protocols for docking and virtual screening of covalent ligands.
- 229(a) Kathman, S. G.; Xu, Z.; Statsyuk, A. V. A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases. J. Med. Chem. 2014, 57, 4969– 4974, DOI: 10.1021/jm500345q[ACS Full Text.], [CAS], Google Scholar229ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXovVWiur0%253D&md5=39dee964ac1ba26ed373eedbd86102acA Fragment-Based Method to Discover Irreversible Covalent Inhibitors of Cysteine ProteasesKathman, Stefan G.; Xu, Ziyang; Statsyuk, Alexander V.Journal of Medicinal Chemistry (2014), 57 (11), 4969-4974CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. Acrylamides, acylaminoacrylates, vinylsulfonamides, and acylaminopropenyl sulfones were prepd. and the dependence of their rates of reaction with N-acetylcysteine Me ester on their structure was detd.; of the compds. tested, the rate of Michael addn. of N-acetylcysteine Me ester to acylaminoacrylates depended least on the acyl moiety. A library of 100 fragment-substituted acylaminoacrylates was prepd.; addn. of subsets of the library to papain followed by mass spectrometric anal. identified three acylaminoacrylates which selectively reacted with the cysteine protease papain. The kinetics of the inhibition of papain by the acylaminoacrylates, the effect of known inhibitors of papain on its inhibition by the acylaminoacrylates, and the lack of inhibition of other cysteine proteases (human rhinovirus 3C protease, the catalytic domain of the deubiquitinase USP08, and the E2 ubiquitin-conjugating enzyme UbcH7) by the acylaminoacrylates supported their identification as selective and irreversible papain inhibitors.(b) Kathman, S. G.; Span, I.; Smith, A. T.; Xu, Z.; Zhan, J.; Rosenzweig, A. C.; Statsyuk, A. V. A small molecule that switches a ubiquitin ligase from a processive to a distributive enzymatic mechanism. J. Am. Chem. Soc. 2015, 137, 12442– 12445, DOI: 10.1021/jacs.5b06839[ACS Full Text], [CAS], Google Scholar229bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2mtLvO&md5=bf3532047b8f09399e3bf6dcc87ff50dA Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic MechanismKathman, Stefan G.; Span, Ingrid; Smith, Aaron T.; Xu, Ziyang; Zhan, Jennifer; Rosenzweig, Amy C.; Statsyuk, Alexander V.Journal of the American Chemical Society (2015), 137 (39), 12442-12445CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacol. probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochem. mutations or small mols. switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallog. and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
- 230Johansson, H.; Tsai, Y. I.; Fantom, K.; Chung, C. W.; Kümper, S.; Martino, L.; Thomas, D. A.; Eberl, H. C.; Muelbaier, M.; House, D.; Rittinger, K. Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP. J. Am. Chem. Soc. 2019, 141, 2703, DOI: 10.1021/jacs.8b13193[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVahtrY%253D&md5=c5ca10ce463f1382a7621d28e8b7ba11Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIPJohansson, Henrik; Isabella Tsai, Yi-Chun; Fantom, Ken; Chung, Chun-Wa; Kumper, Sandra; Martino, Luigi; Thomas, Daniel A.; Eberl, H. Christian; Muelbaier, Marcel; House, David; Rittinger, KatrinJournal of the American Chemical Society (2019), 141 (6), 2703-2712CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and alterations in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signaling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multiprotein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochem. ubiquitination assays, chem. synthesis, and protein crystallog. to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics, we demonstrate that these compds. effectively penetrate mammalian cells to label and inhibit HOIP and NF-κB activation, making them suitable hits for the development of selective probes to study LUBAC biol. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compds. for challenging targets, which holds promise to be a general approach for the development of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.
- 231Lavogina, D.; Lust, M.; Viil, I.; König, N.; Raidaru, G.; Rogozina, J.; Enkvist, E.; Uri, A.; Bossemeyer, D. Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases. J. Med. Chem. 2009, 52, 308– 321, DOI: 10.1021/jm800797n[ACS Full Text], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFWmug%253D%253D&md5=e50dd17444e6d94c9193ee5a91d0e0c9Structural Analysis of ARC-Type Inhibitor (ARC-1034) Binding to Protein Kinase A Catalytic Subunit and Rational Design of Bisubstrate Analogue Inhibitors of Basophilic Protein KinasesLavogina, Darja; Lust, Marje; Viil, Indrek; Konig, Norbert; Raidaru, Gerda; Rogozina, Jevgenia; Enkvist, Erki; Uri, Asko; Bossemeyer, DirkJournal of Medicinal Chemistry (2009), 52 (2), 308-321CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The crystal structure of a complex of the catalytic subunit (type α) of cAMP-dependent protein kinase (PKA Cα) with ARC-type inhibitor (ARC-1034), the presumed lead scaffold of previously reported adenosine-oligo-arginine conjugate-based (ARC-type) inhibitors, was solved. Structural elements important for interaction with the kinase were established with specifically modified derivs. of the lead compd. On the basis of this knowledge, a new generation of inhibitors, conjugates of adenosine-4'-dehydroxymethyl-4'-carboxylic acid moiety and oligo(D-arginine), was developed with inhibitory consts. well into the subnanomolar range. The structural determinants of selectivity of the new compds. were established in assays with ROCK-II and PKBγ.
- 232Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A. M.; Wright, G. D.; Auclair, K. Synthesis and structure-activity relationships of truncated bisubstrate inhibitors of aminoglycoside 6′-N-acetyltransferases. J. Med. Chem. 2006, 49, 5273– 5281, DOI: 10.1021/jm060732n[ACS Full Text], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnsF2gsr4%253D&md5=029f6fb9997964100f1316de2e44c666Synthesis and Structure-Activity Relationships of Truncated Bisubstrate Inhibitors of Aminoglycoside 6'-N-AcetyltransferasesGao, Feng; Yan, Xuxu; Shakya, Tushar; Baettig, Oliver M.; Ait-Mohand-Brunet, Samia; Berghuis, Albert M.; Wright, Gerard D.; Auclair, KarineJournal of Medicinal Chemistry (2006), 49 (17), 5273-5281CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Truncated aminoglycoside-CoA bisubstrate analogs, e.g I, were efficiently prepd. using a convergent approach where the amine and the thiol are coupled in one-pot chemo- and regioselective coupling reaction with the addn. of a linker, without the need for protecting groups. These derivs. were tested for their effect on the activity of the resistance-causing enzyme aminoglycoside 6'-N-acetyltransferase Ii, and key structure-activity relationships are reported. Moreover, one of the inhibitors is able to block aminoglycoside resistance in cells expressing this enzyme.
- 233Bockman, M. R.; Kalinda, A. S.; Petrelli, R.; De la Mora-Rey, T.; Tiwari, D.; Liu, F.; Dawadi, S.; Nandakumar, M.; Rhee, K. Y.; Schnappinger, D.; Finzel, B. C.; Aldrich, C. C. Targeting mycobacterium tuberculosis biotin protein ligase (MtBPL) with nucleoside-based bisubstrate adenylation inhibitors. J. Med. Chem. 2015, 58, 7349– 7369, DOI: 10.1021/acs.jmedchem.5b00719[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOqu73O&md5=ff3aa92e11c9558f140837fe547c2649Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bi-substrate Adenylation InhibitorsBockman, Matthew R.; Kalinda, Alvin S.; Petrelli, Riccardo; De la Mora-Rey, Teresa; Tiwari, Divya; Liu, Feng; Dawadi, Surrendra; Nandakumar, Madhumitha; Rhee, Kyu Y.; Schnappinger, Dirk; Finzel, Barry C.; Aldrich, Courtney C.Journal of Medicinal Chemistry (2015), 58 (18), 7349-7369CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic tuberculosis (TB), remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metab. through the post-translational biotinylation of acyl CoA carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compds. were characterized by isothermal titrn. calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Addnl., we obtained high-resoln. co-crystal structures for a majority of the compds. Despite fairly uniform biochem. potency, the whole-cell Mtb activity varied greatly with min. inhibitory concns. (MIC) ranging from 0.78 to >100 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analog over the corresponding C-2'-β analog, consistent with their differential whole-cell activity.
- 234Halby, L.; Menon, Y.; Rilova, E.; Pechalrieu, D.; Masson, V.; Faux, C.; Bouhlel, M. A.; David-Cordonnier, M. H.; Novosad, N.; Aussagues, Y.; Samson, A.; Lacroix, L.; Ausseil, F.; Fleury, L.; Guianvarc’h, D.; Ferroud, C.; Arimondo, P. B. Rational design of bisubstrate-type analogues as inhibitors of DNA methyltransferases in cancer cells. J. Med. Chem. 2017, 60, 4665– 4679, DOI: 10.1021/acs.jmedchem.7b00176[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVGgtLY%253D&md5=91cf15839ca568c0f64987ff079df5e5Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer CellsHalby, Ludovic; Menon, Yoann; Rilova, Elodie; Pechalrieu, Dany; Masson, Veronique; Faux, Celine; Bouhlel, Mohamed Amine; David-Cordonnier, Marie-Helene; Novosad, Natacha; Aussagues, Yannick; Samson, Arnaud; Lacroix, Laurent; Ausseil, Frederic; Fleury, Laurence; Guianvarc'h, Dominique; Ferroud, Clotilde; Arimondo, Paola B.Journal of Medicinal Chemistry (2017), 60 (11), 4665-4679CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly obsd. in cancer and its inhibition by small mols. is promising for their reactivation. Here the authors designed bisubstrate analogs-based inhibitors, by mimicking each substrate, - the S-adenosyl-L-methionine and the deoxycytidine -, and linking them together. This approach resulted in quinazoline-quinoline derivs. as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. The authors highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of CDKN2A promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cells model system, the authors found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter and the reactivation of a reporter gene.
- 235Babault, N.; Allali-Hassani, A.; Li, F.; Fan, J.; Yue, A.; Ju, K.; Liu, F.; Vedadi, M.; Liu, J.; Jin, J. Discovery of bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT). J. Med. Chem. 2018, 61, 1541– 1551, DOI: 10.1021/acs.jmedchem.7b01422[ACS Full Text], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVOruw%253D%253D&md5=50e23e5f60beb64c184f6eadc6a75883Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling; Fan, Jie; Yue, Alex; Ju, Kevin; Liu, Feng; Vedadi, Masoud; Liu, Jing; Jin, JianJournal of Medicinal Chemistry (2018), 61 (4), 1541-1551CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-contg. compds. using the cofactor S-5'-adenosyl-L-methionine (SAM) as the Me group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays important role in physiol. and pathophysiol. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-mol. NNMT inhibitors are valuable chem. tools for testing biol. and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6), and characterization of this inhibitor in biochem., biophys., kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-mol. inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.
- 236Cinelli, M. A.; Li, H.; Chreifi, G.; Poulos, T. L.; Silverman, R. B. Nitrile in the hole: Discovery of a small auxiliary pocket in neuronal nitric oxide synthase leading to the development of potent and selective 2-aminoquinoline Inhibitors. J. Med. Chem. 2017, 60, 3958– 3978, DOI: 10.1021/acs.jmedchem.7b00259[ACS Full Text], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt1CgsL4%253D&md5=d28b9e3c938b76a20895b2558acef929Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline InhibitorsCinelli, Maris A.; Li, Huiying; Chreifi, Georges; Poulos, Thomas L.; Silverman, Richard B.Journal of Medicinal Chemistry (2017), 60 (9), 3958-3978CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compds. had decreased permeability, low human nNOS activity, and low selectivity vs. human eNOS. In this study, 5-substituted Ph ether-linked aminoquinolines and derivs. were synthesized and assayed against purified NOS isoforms. 5-Cyano compds. are esp. potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compds.
- 237Ye, S.; Loll, B.; Berger, A. A.; Mülow, U.; Alings, C.; Wahl, M. C.; Koksch, B. Fluorine teams up with water to restore inhibitor activity to mutant BPTI. Chem. Sci. 2015, 6, 5246– 5254, DOI: 10.1039/C4SC03227F[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVSgsbrO&md5=21a963abeae8a26436052898a6dd0edbFluorine teams up with water to restore inhibitor activity to mutant BPTIYe, Shijie; Loll, Bernhard; Berger, Allison Ann; Muelow, Ulrike; Alings, Claudia; Wahl, Markus Christian; Koksch, BeateChemical Science (2015), 6 (9), 5246-5254CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Introducing fluorine into mols. has a wide range of effects on their physicochem. properties, often desirable but in most cases unpredictable. The fluorine atom imparts the C-F bond with low polarizability and high polarity, and significantly affects the behavior of neighboring functional groups, in a covalent or noncovalent manner. Here, we report that fluorine, present in the form of a single fluoroalkyl amino acid side chain in the P1 position of the well-characterized serine-protease inhibitor BPTI, can fully restore inhibitor activity to a mutant that contains the corresponding hydrocarbon side chain at the same site. High resoln. crystal structures were obtained for four BPTI variants in complex with bovine β-trypsin, revealing changes in the stoichiometry and dynamics of water mols. in the S1 subsite. These results demonstrate that the introduction of fluorine into a protein environment can result in "chem. complementation" that has a significantly favorable impact on protein-protein interactions.
- 238Seo, J.; Igarashi, J.; Li, H.; Martasek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water. J. Med. Chem. 2007, 50, 2089– 2099, DOI: 10.1021/jm061305c[ACS Full Text], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktVyhur8%253D&md5=0a804fb557c4b7f81b9153e0f68e0cc0Structure-based design and synthesis of Nω-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric Oxide synthase. Displacement of the heme structural waterSeo, Jiwon; Igarashi, Jotato; Li, Huiying; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.Journal of Medicinal Chemistry (2007), 50 (9), 2089-2099CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the prodn. of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (I) (R1 = H) and (II) (R2 = H), led to the discovery of a conserved structural water mol. that was hydrogen bonded between the two heme propionates and the inhibitors. On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of II (R2 = H) or to the secondary amine nitrogen of I (R1 = H), the inhibitor mols. could displace the structural water mol. and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogs I (R1 = OH, NH2) and II (R2 = OH) which have either an N-hydroxyl or N-amino donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors I (R1 = OH) and II (R2 = OH) bound verified that the N-hydroxyl group had, indeed, displaced the structural water mol. and provided a direct interaction with the heme propionate moiety. Surprisingly, in vitro activity assay results indicated that the addn. of a hydroxyl group I (R1 = OH) only increased the potency slightly against the neuronal isoform over the parent compd. I (R1 = H). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.
- 239Fornabaio, M.; Spyrakis, F.; Mozzarelli, A.; Cozzini, P.; Abraham, D. J.; Kellogg, G. E. Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. J. Med. Chem. 2004, 47, 4507– 4516, DOI: 10.1021/jm030596b[ACS Full Text], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVeitbY%253D&md5=490841fb8fea47e37d57b4bd0b530fd3Simple, Intuitive Calculations of Free Energy of Binding for Protein-Ligand Complexes. 3. The Free Energy Contribution of Structural Water Molecules in HIV-1 Protease ComplexesFornabaio, Micaela; Spyrakis, Francesca; Mozzarelli, Andrea; Cozzini, Pietro; Abraham, Donald J.; Kellogg, Glen E.Journal of Medicinal Chemistry (2004), 47 (18), 4507-4516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural water mols. within protein active sites are relevant for ligand-protein recognition because they modify the active site geometry and contribute to binding affinity. An anal. of the interactions between 23 ligands and dimeric HIV-1 protease is reported. The x-ray structures of these complexes show the presence of four types of structural water mols.: water 301 (on the symmetry axis), water 313, water 313bis, and peripheral waters. Except for water 301, these are generally complemented with a symmetry-related set. The GRID program was used both for checking water locations and for placing water mols. that appear to be missing from the complexes due to crystallog. uncertainty. Hydropathic anal. of the energetic contributions using HINT indicates a significant improvement of the correlation between HINT scores and the exptl. detd. binding consts. when the appropriate bridging water mols. are taken into account. In the absence of water r2 = 0.30 with a std. error of ± 1.30 kcal mol-1 and when the energetic contributions of the constrained waters are included r2 = 0.61 with a std. error of ± 0.98 kcal mol-1. HINT was shown to be able to map quant. the contribution of individual structural waters to binding energy. The order of relevance for the various types of water is water 301 > water 313 > water 313bis > peripheral waters. Thus, to obtain the most reliable free energy predictions, the contributions of structural water mols. should be included. However, care must be taken to include the effects of water mols. that add information value and not just noise.
- 240(a) Chong, P. Y.; Shotwell, J. B.; Miller, J. F.; Price, D. J.; Maynard, A.; Voitenleitner, C.; Mathis, A.; Williams, S.; Pouliot, J.; Creech, K.; Wang, F.; Fang, J. M.; Zhang, H.; Tai, V.; Turner, E.; Kahler, K. M.; Crosby, R.; Peat, A. J. Design of N-benzoxaborole benzofuran GSK8175 - Optimization of human PK inspired by metabolites of a failed clinical HCV inhibitor. J. Med. Chem. 2019, 62, 3254, DOI: 10.1021/acs.jmedchem.8b01719[ACS Full Text.], [CAS], Google Scholar240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFCrsL8%253D&md5=3c8cbff5f4273f2cf43da3ec14e93f2cDesign of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV InhibitorChong, Pek Y.; Shotwell, J. Brad; Miller, John; Price, Daniel J.; Maynard, Andy; Voitenleitner, Christian; Mathis, Amanda; Williams, Shawn; Pouliot, Jeffrey J.; Creech, Katrina; Wang, Feng; Fang, Jing; Zhang, Huichang; Tai, Vincent W.-F.; Turner, Elizabeth; Kahler, Kirsten M.; Crosby, Renae; Peat, Andrew J.Journal of Medicinal Chemistry (2019), 62 (7), 3254-3267CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidn. resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities assocd. with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclin. species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystd. with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water mols. and the first evidence of boronate complex formation within the binding pocket. In clin. studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidn. would improve human pharmacokinetics and lower efficacious doses relative to 1.(b) Zhan, P.; Kang, D.; Liu, X. Resurrecting the condemned: Identification of N-benzoxaborole benzofuran GSK8175 as a clinical candidate with reduced metabolic liability. J. Med. Chem. 2019, 62, 3251, DOI: 10.1021/acs.jmedchem.9b00415[ACS Full Text], [CAS], Google Scholar240bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVGqtbg%253D&md5=5e49c814c668f48322097841bb1f593bResurrecting the condemned: identification of N-benzoxaborole benzofuran GSK8175 as a clinical candidate with reduced metabolic liabilityZhan, Peng; Kang, Dongwei; Liu, XinyongJournal of Medicinal Chemistry (2019), 62 (7), 3251-3253CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Recently, in a program designed to improve the metabolic stability of the HCV inhibitor GSK5852, N-benzoxaborole benzofuran (GSK8175) emerged as a clin. candidate that not only retains the broad-spectrum activity against HCV subgenomic replicons but is free of the N-benzylboronic acid structure, which is a metabolic liability, and probably the cause of low in vivo clearance in preclin. species. This Viewpoint discusses some medicinal chem. issues involved in the identification of GSK8175.
- 241Spyrakis, F.; Ahmed, M. H.; Bayden, A. S.; Cozzini, P.; Mozzarelli, A.; Kellogg, G. E. The roles of water in the protein matrix: a largely untapped resource for drug discovery. J. Med. Chem. 2017, 60, 6781– 6827, DOI: 10.1021/acs.jmedchem.7b00057[ACS Full Text], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVyru7s%253D&md5=1e6f76629bf2eeabf8b491f8814cfc69The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug DiscoverySpyrakis, Francesca; Ahmed, Mostafa H.; Bayden, Alexander S.; Cozzini, Pietro; Mozzarelli, Andrea; Kellogg, Glen E.Journal of Medicinal Chemistry (2017), 60 (16), 6781-6827CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The value of thoroughly understanding the thermodn. specific to a drug discovery/design study is well known. Over the past decade, the crucial roles of water mols. in protein structure, function, and dynamics have also become increasingly appreciated. This Perspective explores water in the biol. environment by adopting its point of view in such phenomena. The prevailing thermodn. models of the past, where water was seen largely in terms of an entropic gain after its displacement by a ligand, are now known to be much too simplistic. We adopt a set of terminol. that describes water mols. as being "hot" and "cold", which we have defined as being easy and difficult to displace, resp. The basis of these designations, which involve both enthalpic and entropic water contributions, are explored in several classes of biomols. and structural motifs. The hallmarks for characterizing water mols. are examd., and computational tools for evaluating water-centric thermodn. are reviewed. This Perspective's summary features guidelines for exploiting water mols. in drug discovery.
- 242Gerstenberger, B. S.; Trzupek, J. D.; Tallant, C.; Fedorov, O.; Filippakopoulos, P.; Brennan, P. E.; Fedele, V.; Martin, S.; Picaud, S.; Rogers, C.; Parikh, M.; Taylor, A.; Samas, B.; O’Mahony, A.; Berg, E.; Pallares, G.; Torrey, A. D.; Treiber, D. K.; Samardjiev, I. J.; Nasipak, B. T.; Padilla-Benavides, T.; Wu, Q.; Imbalzano, A. N.; Nickerson, J. A.; Bunnage, M. E.; Muller, S.; Knapp, S.; Owen, D. R. Identification of a chemical probe for family VIII bromodomains through optimization of a fragment hit. J. Med. Chem. 2016, 59, 4800– 4811, DOI: 10.1021/acs.jmedchem.6b00012[ACS Full Text], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmsl2rs74%253D&md5=6cb73e76a19f7fb44153f8cbfeff9cf6Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment HitGerstenberger, Brian S.; Trzupek, John D.; Tallant, Cynthia; Fedorov, Oleg; Filippakopoulos, Panagis; Brennan, Paul E.; Fedele, Vita; Martin, Sarah; Picaud, Sarah; Rogers, Catherine; Parikh, Mihir; Taylor, Alexandria; Samas, Brian; O'Mahony, Alison; Berg, Ellen; Pallares, Gabriel; Torrey, Adam V.; Treiber, Daniel K.; Samardjiev, Ivan J.; Nasipak, Brian T.; Padilla-Benavides, Teresita; Wu, Qiong; Imbalzano, Anthony N.; Nickerson, Jeffrey A.; Bunnage, Mark E.; Muller, Susanne; Knapp, Stefan; Owen, Dafydd R.Journal of Medicinal Chemistry (2016), 59 (10), 4800-4811CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water mols. that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chem. program that led to PFI-3 from an initial fragment screening hit is described in detail, and addnl. analogs with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacol. characterization of PFI-3 as a chem. probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.
- 243Kuhne, S.; Kooistra, A. J.; Bosma, R.; Bortolato, A.; Wijtmans, M.; Vischer, H. F.; Mason, J. S.; de Graaf, C.; de Esch, I. J.; Leurs, R. Identification of ligand binding hot spots of the histamine H1 receptor following structure-based fragment optimization. J. Med. Chem. 2016, 59, 9047– 9061, DOI: 10.1021/acs.jmedchem.6b00981[ACS Full Text], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFanu7rK&md5=7e9bd27144fcaf11a3176bf717849bcdIdentification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment OptimizationKuhne, Sebastiaan; Kooistra, Albert J.; Bosma, Reggie; Bortolato, Andrea; Wijtmans, Maikel; Vischer, Henry F.; Mason, Jonathan S.; de Graaf, Chris; de Esch, Iwan J. P.; Leurs, RobJournal of Medicinal Chemistry (2016), 59 (19), 9047-9061CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Developments in G protein-coupled receptor (GPCR) structural biol. provide insights into GPCR-ligand binding. Compd. I (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivs. to investigate the roles of: (1) the amine-binding region, (2) the upper and lower arom. region and (3) binding site solvation. SAR anal. showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water mol. from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of I. Deconstruction of I showed that the lower arom. region serves as a secondary binding hot spot. This study demonstrates that an x-ray structure in combination with tool compds., assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
- 244Blanco, B.; Sedes, A.; Peon, A.; Otero, J. M.; van Raaij, M. J.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Exploring the water-binding pocket of the type II dehydroquinase enzyme in the structure-based design of inhibitors. J. Med. Chem. 2014, 57, 3494– 3510, DOI: 10.1021/jm500175z[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2ku7Y%253D&md5=06d1c7306e1937956f3a6420bbab16f3Exploring the water-binding pocket of the type II dehydroquinase enzyme in the structure-based design of inhibitorsBlanco, Beatriz; Sedes, Antia; Peon, Antonio; Otero, Jose M.; van Raaij, Mark J.; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2014), 57 (8), 3494-3510CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural and computational studies to explore the WAT1 binding pocket in the structure-based design of inhibitors against the type II dehydroquinase (DHQ2) enzyme are reported. The crystal structures of DHQ2 from M. tuberculosis in complex with four of the reported compds. are described. The electrostatic interaction obsd. between the guanidinium group of the essential arginine and the carboxylate group of one of the inhibitors in the reported crystal structures supports the recently suggested role of this arginine as the residue that triggers the release of the product from the active site. The results of the structural and mol. dynamics simulation studies revealed that the inhibitory potency is favored by promoting interactions with WAT1 and the residues located within this pocket and, more importantly, by avoiding situations where the ligands occupy the WAT1 binding pocket. The new insights can be used to advantage in the structure-based design of inhibitors.
- 245Wright, Z. V. F.; Wu, N. C.; Kadam, R. U.; Wilson, I. A.; Wolan, D. W. Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin. Bioorg. Med. Chem. Lett. 2017, 27, 3744– 3748, DOI: 10.1016/j.bmcl.2017.06.074[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCgtbvK&md5=036be03e9d7f3959120c772fa87f2317Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutininWright, Zoe V. F.; Wu, Nicholas C.; Kadam, Rameshwar U.; Wilson, Ian A.; Wolan, Dennis W.Bioorganic & Medicinal Chemistry Letters (2017), 27 (16), 3744-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We detd. the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compds. Addn. of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water mol. in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogs represent novel leads to yield more potent compds. against hemagglutinin that block viral entry.
- 246Mosure, S.; Shang, J.; Eberhardt, J.; Brust, R.; Zheng, J.; Griffin, P. R.; Forli, S.; Kojetin, D. J. Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone. J. Med. Chem. 2019, 62, 2008, DOI: 10.1021/acs.jmedchem.8b01573[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFSjt78%253D&md5=8986f54f42e74d9714b9e31826b52e7bStructural basis of altered potency and efficacy displayed by a major in vivo metabolite of the Antidiabetic PPARγ drug pioglitazoneMosure, Sarah A.; Shang, Jinsai; Eberhardt, Jerome; Brust, Richard; Zheng, Jie; Griffin, Patrick R.; Forli, Stefano; Kojetin, Douglas J.Journal of Medicinal Chemistry (2019), 62 (4), 2008-2023CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallog. and mol. docking anal. of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochem. phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry anal. coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
- 247Thomaston, J. L.; Polizzi, N. F.; Konstantinidi, A.; Wang, J.; Kolocouris, A.; DeGrado, W. F. Inhibitors of the M2 proton channel engage and disrupt transmembrane networks of hydrogen-bonded waters. J. Am. Chem. Soc. 2018, 140, 15219, DOI: 10.1021/jacs.8b06741[ACS Full Text], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1ensLfK&md5=5d6f01de165142f3494bc4f12a8ced9aInhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded WatersThomaston, Jessica L.; Polizzi, Nicholas F.; Konstantinidi, Athina; Wang, Jun; Kolocouris, Antonios; DeGrado, William F.Journal of the American Chemical Society (2018), 140 (45), 15219-15226CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-mol. approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small mols. can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using x-ray crystallog. have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resoln. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. These drug-bound complexes provide the first high-resoln. structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.
- 248Geist, L.; Mayer, M.; Cockcroft, X.-L.; Wolkerstorfer, B.; Kessler, D.; Engelhardt, H.; McConnell, D. B.; Konrat, R. Direct NMR probing of hydration shells of protein ligand interfaces and its application to drug design. J. Med. Chem. 2017, 60, 8708– 8715, DOI: 10.1021/acs.jmedchem.7b00845[ACS Full Text], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2js7%252FJ&md5=36b9cb69d63d216eedaa081d3d2605b8Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug DesignGeist, Leonhard; Mayer, Moriz; Cockcroft, Xiao-Ling; Wolkerstorfer, Bernhard; Kessler, Dirk; Engelhardt, Harald; McConnell, Darryl B.; Konrat, RobertJournal of Medicinal Chemistry (2017), 60 (21), 8708-8715CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fragment-based drug design exploits initial screening of low mol. wt. compds. and their concomitant affinity improvement. The multitude of possible chem. modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodol. (LOGSY titrn.) that allows the detn. of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addn. of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodol. and in contrast to conventional ligand-based methods is the independence of the mol. wt. of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain contg. protein 4, a prominent cancer target in pharmaceutical industry.
- 249Murphy, R. B.; Repasky, M. P.; Greenwood, J. R.; Tubert-Brohman, I.; Jerome, S.; Annabhimoju, R.; Boyles, N. A.; Schmitz, C. D.; Abel, R.; Farid, R.; Friesner, R. A. WScore: A flexible and accurate treatment of explicit water molecules in ligand-receptor docking. J. Med. Chem. 2016, 59, 4364– 4384, DOI: 10.1021/acs.jmedchem.6b00131[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Gqtr4%253D&md5=dcb2bc320a1bffe608531c4aa01666bbWScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand-Receptor DockingMurphy, Robert B.; Repasky, Matthew P.; Greenwood, Jeremy R.; Tubert-Brohman, Ivan; Jerome, Steven; Annabhimoju, Ramakrishna; Boyles, Nicholas A.; Schmitz, Christopher D.; Abel, Robert; Farid, Ramy; Friesner, Richard A.Journal of Medicinal Chemistry (2016), 59 (9), 4364-4384CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have developed a new methodol. for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water mols. The locations and thermodn. of the waters are derived from a WaterMap mol. dynamics simulation. The water structure is employed to provide an at. level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to exptl. data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.
- 250Peach, M. L.; Tan, N.; Choyke, S. J.; Giubellino, A.; Athauda, G.; Burke, T. R., Jr.; Nicklaus, M. C.; Bottaro, D. P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem. 2009, 52, 943– 951, DOI: 10.1021/jm800791f[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFGrsw%253D%253D&md5=1b814fef6ce3ceb055f899379fdb8d8cDirected Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual ScreeningPeach, Megan L.; Tan, Nelly; Choyke, Sarah J.; Giubellino, Alessio; Athauda, Gagani; Burke, Terrence R., Jr.; Nicklaus, Marc C.; Bottaro, Donald P.Journal of Medicinal Chemistry (2009), 52 (4), 943-951CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-mol. inhibitors of oncogenic tyrosine kinases (TK) has led to well-tolerated, targeted therapies for a growing no. of cancer types. To identify selective Met TK inhibitors, we used a high-throughput virtual screen of the 13.5 million compd. ChemNavigator database to find compds. most likely to bind to the Met ATP binding site and to form several crit. interactions with binding site residues predicted to stabilize the kinase domain in its inactive conformation. Subsequent biol. screening of 70 in silico hit structures using cell-free and intact cell assays identified three active compds. with micromolar IC50 values. The predicted binding modes and target selectivity of these compds. are discussed and compared to other known Met TK inhibitors.
- 251Klüter, S.; Grutter, C.; Naqvi, T.; Rabiller, M.; Simard, J. R.; Pawar, V.; Getlik, M.; Rauh, D. Displacement assay for the detection of stabilizers of inactive kinase conformations. J. Med. Chem. 2010, 53, 357– 367, DOI: 10.1021/jm901297e[ACS Full Text], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKhs7fO&md5=4bee62eba370bd4b7c40ba5ab6bd2be2Displacement Assay for the Detection of Stabilizers of Inactive Kinase ConformationsKlueter, Sabine; Gruetter, Christian; Naqvi, Tabassum; Rabiller, Matthias; Simard, Jeffrey R.; Pawar, Vijaykumar; Getlik, Matthaeus; Rauh, DanielJournal of Medicinal Chemistry (2010), 53 (1), 357-367CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeting protein kinases with small mols. outside the highly conserved ATP pocket to stabilize inactive kinase conformations is becoming a more desirable approach in kinase inhibitor research, since these mols. have advanced pharmacol. properties compared to compds. exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors are often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyrazolourea type III inhibitor and enzyme fragment complementation (EFC) technol. that is suitable to screen stabilizers of enzymically inactive kinases. To validate this assay system, we report the binding characteristics of a series of kinase inhibitors to inactive p38α and JNK2. Addnl., we present protein X-ray crystallog. studies to examine the binding modes of potent quinoline-based DFG-out binders in p38α.
- 252(a) Whelligan, D. K.; Solanki, S.; Taylor, D.; Thomson, D. W.; Cheung, K. M.; Boxall, K.; Mas-Droux, C.; Barillari, C.; Burns, S.; Grummitt, C. G.; Collins, I.; van Montfort, R. L.; Aherne, G. W.; Bayliss, R.; Hoelder, S. Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization. J. Med. Chem. 2010, 53, 7682– 7698, DOI: 10.1021/jm1008727[ACS Full Text.], [CAS], Google Scholar252ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Krs7nI&md5=d1a4af6869319bed0a340e8ff7db4397Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural CharacterizationWhelligan, Daniel K.; Solanki, Savade; Taylor, Dawn; Thomson, Douglas W.; Cheung, Kwai-Ming J.; Boxall, Kathy; Mas-Droux, Corine; Barillari, Caterina; Burns, Samantha; Grummitt, Charles G.; Collins, Ian; van Montfort, Rob L. M.; Aherne, G. Wynne; Bayliss, Richard; Hoelder, SwenJournal of Medicinal Chemistry (2010), 53 (21), 7682-7698CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine I, compds. with improved activity were identified using structure-based design. Our structural biol. investigations reveal two notable observations. First, I and related compds. bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.(b) Colombano, G.; Caldwell, J. J.; Matthews, T. P.; Bhatia, C.; Joshi, A.; McHardy, T.; Mok, N. Y.; Newbatt, Y.; Pickard, L.; Strover, J.; Hedayat, S.; Walton, M. I.; Myers, S.; Jones, A. M.; Saville, H.; McAndrew, C.; Burke, R.; Eccles, S.; Davies, F.; Bayliss, R.; Collins, I. Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1α kinase-endoribonuclease. J. Med. Chem. 2019, 62, 2447, DOI: 10.1021/acs.jmedchem.8b01721[ACS Full Text], [CAS], Google Scholar252bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtlSqsr8%253D&md5=9e4f266c35c4c4ec08e72f753b4f58a6Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-EndoribonucleaseColombano, Giampiero; Caldwell, John J.; Matthews, Thomas P.; Bhatia, Chitra; Joshi, Amar; McHardy, Tatiana; Mok, Ngai Yi; Newbatt, Yvette; Pickard, Lisa; Strover, Jade; Hedayat, Somaieh; Walton, Michael I.; Myers, Stephanie M.; Jones, Alan M.; Saville, Harry; McAndrew, Craig; Burke, Rosemary; Eccles, Suzanne A.; Davies, Faith E.; Bayliss, Richard; Collins, IanJournal of Medicinal Chemistry (2019), 62 (5), 2447-2465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compds. with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallog. showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.
- 253Prado, V.; Lence, E.; Maneiro, M.; Vazquez-Ucha, J. C.; Beceiro, A.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Targeting the motion of shikimate kinase: development of competitive inhibitors that stabilize an inactive open conformation of the enzyme. J. Med. Chem. 2016, 59, 5471– 5487, DOI: 10.1021/acs.jmedchem.6b00483[ACS Full Text], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslWiurY%253D&md5=9022076b2c4efd51c65322374dfb7ed7Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the EnzymePrado, Veronica; Lence, Emilio; Maneiro, Maria; Vazquez-Ucha, Juan C.; Beceiro, Alejandro; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2016), 59 (11), 5471-5487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The large conformational changes obsd. by Mol. Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogs interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivs. 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient deriv. in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.
- 254Weisner, J.; Gontla, R.; van der Westhuizen, L.; Oeck, S.; Ketzer, J.; Janning, P.; Richters, A.; Mühlenberg, T.; Fang, Z.; Taher, A.; Jendrossek, V.; Pelly, S. C.; Bauer, S.; van Otterlo, W. A.; Rauh, D. Covalent-allosteric kinase inhibitors. Angew. Chem., Int. Ed. 2015, 54, 10313– 10316, DOI: 10.1002/anie.201502142[Crossref], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKms7fE&md5=9502910ef46da0e7e7ae7d2156e0a292Covalent-Allosteric Kinase InhibitorsWeisner, Joern; Gontla, Rajesh; van der Westhuizen, Leandi; Oeck, Sebastian; Ketzer, Julia; Janning, Petra; Richters, Andre; Muehlenberg, Thomas; Fang, Zhizhou; Taher, Abu; Jendrossek, Verena; Pelly, Stephen C.; Bauer, Sebastian; van Otterlo, Willem A. L.; Rauh, DanielAngewandte Chemie, International Edition (2015), 54 (35), 10313-10316CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homol. (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chem. biol. and medicinal chem. research.
- 255(a) Milroy, L. G.; Bartel, M.; Henen, M. A.; Leysen, S.; Adriaans, J. M.; Brunsveld, L.; Landrieu, I.; Ottmann, C. Stabilizer-guided inhibition of protein-protein interactions. Angew. Chem., Int. Ed. 2015, 54, 15720– 15724, DOI: 10.1002/anie.201507976[Crossref], [CAS], Google Scholar.255ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyht7%252FP&md5=e2db0e3b3f9a155f5ce739e8c7cc6875Stabilizer-Guided Inhibition of Protein-Protein InteractionsMilroy, Lech-Gustav; Bartel, Maria; Henen, Morkos A.; Leysen, Seppe; Adriaans, Joris M. C.; Brunsveld, Luc; Landrieu, Isabelle; Ottmann, ChristianAngewandte Chemie, International Edition (2015), 54 (52), 15720-15724CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The discovery of novel protein-protein interaction (PPI) modulators represents one of the great mol. challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compds., which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, the authors combine x-ray crystallog. data from both stabilizer and inhibitor co-crystal complexes of the adapter protein 14-3-3 to characterize, down to the at. scale, inhibitors of the 14-3-3/Tau PPI, a potential drug target to treat Alzheimer's disease. The most potent compd. notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. The authors' work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14-3-3 and other PPIs.(b) Sijbesma, E.; Hallenbeck, K. K.; Leysen, S.; de Vink, P.; Skora, L.; Jahnke, W.; Brunsveld, L.; Arkin, M. R.; Ottmann, C. Site-directed fragment-based screening for the discovery of protein-protein interaction stabilizers. J. Am. Chem. Soc. 2019, 141, 3524, DOI: 10.1021/jacs.8b11658[ACS Full Text.], [CAS], Google Scholar255bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWjtrY%253D&md5=5e68f397675437fffdca4cc47ed8e078Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction StabilizersSijbesma, Eline; Hallenbeck, Kenneth K.; Leysen, Seppe; de Vink, Pim J.; Skora, Lukasz; Jahnke, Wolfgang; Brunsveld, Luc; Arkin, Michelle R.; Ottmann, ChristianJournal of the American Chemical Society (2019), 141 (8), 3524-3531CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Modulation of protein-protein interactions (PPIs) by small mols. has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon assocn. of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3σ and a peptide derived from Estrogen Receptor α (ERα), an important breast cancer target that is neg. regulated by 14-3-3σ. We identify orthosteric stabilizers that increase 14-3-3/ERα affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERα-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.(c) Andrei, S. A.; de Vink, P.; Sijbesma, E.; Han, L.; Brunsveld, L.; Kato, N.; Ottmann, C.; Higuchi, Y. Rationally designed semisynthetic natural product analogues for stabilization of 14–3-3 protein-protein interactions. Angew. Chem., Int. Ed. 2018, 57, 13470– 13474, DOI: 10.1002/anie.201806584[Crossref], [CAS], Google Scholar255chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslahsL%252FO&md5=c168fae0a4306a739bd4681cb712b701Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein InteractionsAndrei, Sebastian A.; de Vink, Pim; Sijbesma, Eline; Han, Ling; Brunsveld, Luc; Kato, Nobuo; Ottmann, Christian; Higuchi, YusukeAngewandte Chemie, International Edition (2018), 57 (41), 13470-13474CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of mol. dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallog. confirmed the power of the MD-based design approach, revealing the potential for an addnl. hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Addnl., these compds. exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-mol. PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compds., as well as allowing the study of the fundamental principles behind PPI stabilization.
- 256(a) Andrei, S. A.; Sijbesma, E.; Hann, M.; Davis, J.; O’Mahony, G.; Perry, M. W. D.; Karawajczyk, A.; Eickhoff, J.; Brunsveld, L.; Doveston, R. G.; Milroy, L. G.; Ottmann, C. Stabilization of protein-protein interactions in drug discovery. Expert Opin. Drug Discovery 2017, 12, 925– 940, DOI: 10.1080/17460441.2017.1346608[Crossref], [PubMed], [CAS], Google Scholar.256ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOrsbnK&md5=fd6aa91fbca0e69af4a4bdb2f9ce850cStabilization of protein-protein interactions in drug discoveryAndrei, Sebastian A.; Sijbesma, Eline; Hann, Michael; Davis, Jeremy; O'Mahony, Gavin; Perry, Matthew W. D.; Karawajczyk, Anna; Eickhoff, Jan; Brunsveld, Luc; Doveston, Richard G.; Milroy, Lech-Gustav; Ottmann, ChristianExpert Opinion on Drug Discovery (2017), 12 (9), 925-940CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.): PPIs are involved in every disease and specific modulation of these PPIs with small mols. would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-mol. stabilizers of PPIs is underrepresented in drug discovery.: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a no. of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic mols. originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing no. of synthetic small-mol. PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach.: Both the natural products and the growing no. of synthetic mols. show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compd. libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of mols. reviewed here in our opinion justify these efforts.(b) Bier, D.; Thiel, P.; Briels, J.; Ottmann, C. Stabilization of protein-protein interactions in chemical biology and drug discovery. Prog. Biophys. Mol. Biol. 2015, 119, 10– 19, DOI: 10.1016/j.pbiomolbio.2015.05.002[Crossref], [PubMed], [CAS], Google Scholar.256bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKmsb3F&md5=8a51dfc8088641b0bfa658250cd6117aStabilization of Protein-Protein Interactions in chemical biology and drug discoveryBier, David; Thiel, Philipp; Briels, Jeroen; Ottmann, ChristianProgress in Biophysics & Molecular Biology (2015), 119 (1), 10-19CODEN: PBIMAC; ISSN:0079-6107. (Elsevier Ltd.)A review. More than 300,000 Protein-Protein Interactions (PPIs) can be found in human cells. This no. is significantly larger than the no. of single proteins, which are the classical targets for pharmacol. intervention. Hence, specific and potent modulation of PPIs by small, drug-like mols. would tremendously enlarge the "druggable genome" enabling novel ways of drug discovery for essentially every human disease. This strategy is esp. promising in diseases with difficult targets like intrinsically disordered proteins or transcription factors, for example neurodegeneration or metabolic diseases. Whereas the potential of PPI modulation has been recognized in terms of the development of inhibitors that disrupt or prevent a binary protein complex, the opposite (or complementary) strategy to stabilize PPIs has not yet been realized in a systematic manner. This fact is rather surprising given the no. of impressive natural product examples that confer their activity by stabilizing specific PPIs. In addn., in recent years more and more examples of synthetic mols. are being published that work as PPI stabilizers, despite the fact that in the majority they initially have not been designed as such. Here, we describe examples from both the natural products as well as the synthetic mols. advocating for a stronger consideration of the PPI stabilization approach in chem. biol. and drug discovery.(c) Giordanetto, F.; Schäfer, A.; Ottmann, C. Stabilization of protein-protein interactions by small molecules. Drug Discovery Today 2014, 19, 1812– 1821, DOI: 10.1016/j.drudis.2014.08.005[Crossref], [PubMed], [CAS], Google Scholar.256chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVyhtrnE&md5=1b4a81a6f84e391515f992ccb0454566Stabilization of protein-protein interactions by small moleculesGiordanetto, Fabrizio; Schaefer, Anja; Ottmann, ChristianDrug Discovery Today (2014), 19 (11), 1812-1821CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Protein-protein interactions (PPIs) are implicated in every disease and mastering the ability to influence PPIs with small mols. would considerably enlarge the druggable genome. Whereas inhibition of PPIs has repeatedly been shown to work successfully, targeted stabilization of PPIs is underrepresented in the literature. This is all the more surprising because natural products like FK506, rapamycin, brefeldin, forskolin and fusicoccin confer their physiol. activity by stabilizing specific PPIs. However, recently a no. of very interesting synthetic mols. have been reported from drug discovery projects that indeed achieve their desired activities by stabilizing either homo- or hetero-oligomeric complexes of their target proteins.(d) Thiel, P.; Kaiser, M.; Ottmann, C. Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery?. Angew. Chem., Int. Ed. 2012, 51, 2012– 2018, DOI: 10.1002/anie.201107616[Crossref], [CAS], Google Scholar256dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCrsbk%253D&md5=7b08cfbf9af0b49cdf36e739c907c88aSmall-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery?Thiel, Philipp; Kaiser, Markus; Ottmann, ChristianAngewandte Chemie, International Edition (2012), 51 (9), 2012-2018CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The modulation of protein-protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clin. studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biol. contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI-stabilizing natural products have already found application as important drugs. Moreover, directed small-mol. stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs.
- 257Verteramo, M. L.; Stenström, O.; Ignjatović, M. M.; Caldararu, O.; Olsson, M. A.; Manzoni, F.; Leffler, H.; Oksanen, E.; Logan, D. T.; Nilsson, U. J.; Ryde, U.; Akke, M. Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding. J. Am. Chem. Soc. 2019, 141, 2012– 2026, DOI: 10.1021/jacs.8b11099[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslOitg%253D%253D&md5=b9656b2364586b09f0291f8c75728f6dInterplay between conformational entropy and solvation entropy in protein-ligand bindingVerteramo, Maria Luisa; Stenstroem, Olof; Ignjatovic, Majda Misini; Caldararu, Octav; Olsson, Martin A.; Manzoni, Francesco; Leffler, Hakon; Oksanen, Esko; Logan, Derek T.; Nilsson, Ulf J.; Ryde, Ulf; Akke, MikaelJournal of the American Chemical Society (2019), 141 (5), 2012-2026CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Understanding the driving forces underlying mol. recognition is of fundamental importance in chem. and biol. The challenge is to unravel the binding thermodn. into sep. contributions and to interpret these in mol. terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here, we pinpointed the mol. determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titrn. calorimetry, x-ray crystallog., NMR relaxation, and mol. dynamics (MD) simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chem. potential in the unbound state, we reduced the problem of dissecting the thermodn. to a comparison of the 2 protein-ligand complexes. While the free energies of binding were nearly equal for the R and S diastereomers, greater differences were obsd. for the enthalpy and entropy, which consequently exhibited compensatory behavior, ΔΔH°(R - S) = -5 ± 1 kJ/mol and -TΔΔS°(R - S) = 3 ± 1 kJ/mol. NMR relaxation expts. and MD simulations indicated that the protein in complex with the S-stereoisomer had greater conformational entropy than in the R-complex. GIST calcns. revealed addnl., but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.
- 258Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.; Garbaccio, R. M.; Terrett, N. K.; Tillyer, R. D.; Truppo, M. D.; Parmee, E. R. The importance of synthetic chemistry in the pharmaceutical industry. Science 2019, 363, eaat0805, DOI: 10.1126/science.aat0805
- 259(a) Nielsen, T. E.; Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem., Int. Ed. 2008, 47, 48– 56, DOI: 10.1002/anie.200703073[Crossref], [CAS], Google Scholar.259ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFClug%253D%253D&md5=c921b54ae246a3e711c7dd034e130b1cTowards the optimal screening collection. A synthesis strategyNielsen, Thomas E.; Schreiber, Stuart L.Angewandte Chemie, International Edition (2008), 47 (1), 48-56CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The development of effective small-mol. probes and drugs entails at least three stages: (1) a discovery phase, often requiring the synthesis and screening of candidate compds.; (2) an optimization phase, requiring the synthesis and anal. of structural variants; (3) and a manufg. phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while inhouse medicinal and process chemists perform the second and third development stages, resp. The coordinated planning of these activities in advance of the first small-mol. screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, were avoided with advance planning. Therefore, a challenge for synthetic chem. is to develop a new kind of chem. that yields a screening collection comprising small mols. that increase the probability of success in all three phase. Although this transformative chem. remains elusive, progress is being made. Herein, the authors review a newly emerging strategy in diversity-oriented small-mol. synthesis that may have the potential to achieve these challenging goals.(b) Gerry, C. J.; Schreiber, S. L. Chemical probes and drug leads from advances in synthetic planning and methodology. Nat. Rev. Drug Discovery 2018, 17, 333– 352, DOI: 10.1038/nrd.2018.53[Crossref], [PubMed], [CAS], Google Scholar259bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsFCnsbs%253D&md5=cb42a063221707b3bf60710ffd62e564Chemical probes and drug leads from advances in synthetic planning and methodologyGerry, Christopher J.; Schreiber, Stuart L.Nature Reviews Drug Discovery (2018), 17 (5), 333-352CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)A review. Screening of small-mol. libraries is a productive method for identifying both chem. probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chem. space efficiently by populating small-mol. libraries with compds. contg. structural features that are typically under-represented in com. available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chem., and we illustrate the impact of the resultant chem. probes and drug leads in a wide range of diseases.
- 260Dömling, A.; Wang, W.; Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev. 2012, 112, 3083– 135, DOI: 10.1021/cr100233r[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1ehsbg%253D&md5=09577e3204db313fdb16807df21ab724Chemistry and Biology Of Multicomponent ReactionsDomling, Alexander; Wang, Wei; Wang, KanChemical Reviews (Washington, DC, United States) (2012), 112 (6), 3083-3135CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The authors discuss the usefulness of multicomponent reactions (MCR) in medicinal chem. for drug discovery purposes. An advantage of MCR chem. is the very large chem. space, probably the largest available chem. space for drug discovery and medicinal chem. purposes. This also poses very high demands for the right choice of the discovery strategy, for example, high throughput screening or structure-based design. A promising and complementary strategy which leverages the strength of MCR chem. is the use of computation screening and genetic algorithms. In addn., MCRs can be of great value in natural product total synthesis.
- 261Wagner, B. K.; Schreiber, S. L. The power of sophisticated phenotypic screening and modern mechanism-of-action methods. Cell Chem. Biol. 2016, 23, 3– 9, DOI: 10.1016/j.chembiol.2015.11.008[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlSqsb4%253D&md5=e3219e156466fa5a32b2cb4bf6869a90The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action MethodsWagner, Bridget K.; Schreiber, Stuart L.Cell Chemical Biology (2016), 23 (1), 3-9CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)The enthusiasm for phenotypic screening as an approach for small-mol. discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clin. relevant biol. in cell culture. Of course, a major historical barrier to using phenotypic assays in chem. biol. has been the challenge in detg. the mechanism of action (MoA) for compds. of interest. With the combination of medically inspired phenotypic screening and the development of modern MoA methods, we can now start implementing this approach in chem. probe and drug discovery. In this Perspective, we highlight recent advances in phenotypic readouts and MoA detn. by discussing several case studies in which both activities were required for understanding the chem. biol. involved and, in some cases, advancing toward clin. development.
- 262Churcher, I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones?. J. Med. Chem. 2018, 61, 444– 452, DOI: 10.1021/acs.jmedchem.7b01272[ACS Full Text], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWqtbvJ&md5=e60f1777de8bd860c5001137d8583f1fProtac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?Churcher, IanJournal of Medicinal Chemistry (2018), 61 (2), 444-452CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Targeted protein degrdn., using bifunctional small mols. (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degrdn. concepts, and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery - the many potential advantages and outstanding challenges which lie ahead of this technol. are discussed.
- 263(a) Murcko, M. A. What makes a great medicinal chemist? A personal perspective. J. Med. Chem. 2018, 61, 7419– 7424, DOI: 10.1021/acs.jmedchem.7b01445[ACS Full Text.], [CAS], Google Scholar263ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hs7k%253D&md5=375f41f1b14993861de36b2a1e69152fWhat Makes a Great Medicinal Chemist? A Personal PerspectiveMurcko, Mark A.Journal of Medicinal Chemistry (2018), 61 (17), 7419-7424CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Although it is extremely challenging to invent new medicines, I have obsd. that certain behaviors seem to be commonly found among successful medicinal chemists. Those who exhibit most of these character traits are far more likely to bring new drugs into the clinic and onto the market. And, importantly, organizations that encourage these behaviors are far more likely to be successful. These traits can be broken into two categories: "general" and "discipline-specific". General traits are those that are common to all great scientists, while the discipline-specific ones are more specialized behaviors relevant to the medicinal chem. enterprise. I describe these traits, and include some specific examples for each of the medicinal chem. characteristics that I hope will be illustrative. While success in drug discovery is never guaranteed, I believe that embracing and encouraging these behaviors increase the probability of a successful outcome.(b) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. What do medicinal chemists actually make? A 50-year retrospective. J. Med. Chem. 2011, 54, 6405– 6416, DOI: 10.1021/jm200504p[ACS Full Text], [CAS], Google Scholar263bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWjsr7O&md5=33109f9d55967be0d34f377f433621e4What Do Medicinal Chemists Actually Make? A 50-Year RetrospectiveWalters, W. Patrick; Green, Jeremy; Weiss, Jonathan R.; Murcko, Mark A.Journal of Medicinal Chemistry (2011), 54 (19), 6405-6416CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Despite the dramatically increasing costs of pharmaceutical R&D productivity, as measured by the no. of new drugs approved each year, has languished during the past decade. Many different explanations have been proposed to account for this decline, such as increasing regulatory scrutiny, the inherent inefficiency of very large organizations, the pursuit of highly speculative targets identified from genomics, and more objective decision-making about advancing marginal compds. into latest age clin. trials. Another factor often cited to help explain low pharmaceutical productivity is that, paradoxically, many compds. synthesized by medicinal chemists are not "druglike", at least as measured by various criteria. The authors discuss the past, present and perspectives in the development of medicinal chem.
- 264Zhang, P.; Huang, H.; Banerjee, S.; Clarkson, G. J.; Ge, C.; Imberti, C.; Sadler, P. J. Nucleus-targeted organoiridium-albumin conjugate for photodynamic cancer therapy. Angew. Chem., Int. Ed. Engl. 2019, 58, 2350, DOI: 10.1002/anie.201813002[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnitlentg%253D%253D&md5=edb3086d8106864d0d53be83a1592c86Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer TherapyZhang Pingyu; Ge Chen; Zhang Pingyu; Huang Huaiyi; Banerjee Samya; Clarkson Guy J; Imberti Cinzia; Sadler Peter J; Huang HuaiyiAngewandte Chemie (International ed. in English) (2019), 58 (8), 2350-2354 ISSN:.An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high (1) O2 quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50 ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
- 265Hoffer, L.; Voitovich, Y. V.; Raux, B.; Carrasco, K.; Muller, C.; Fedorov, A. Y.; Derviaux, C.; Amouric, A.; Betzi, S.; Horvath, D.; Varnex, A.; Collette, Y.; Combes, S.; Roche, P.; Morelli, X. Integrated strategy for lead optimization based on fragment growing: The diversity-oriented-target-focused-synthesis approach. J. Med. Chem. 2018, 61, 5719– 5732, DOI: 10.1021/acs.jmedchem.8b00653[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSrtLrK&md5=0e5f18636e2b1df24314efa81e67e2b5Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis ApproachHoffer, Laurent; Voitovich, Yuliia V.; Raux, Brigitt; Carrasco, Kendall; Muller, Christophe; Fedorov, Aleksey Y.; Derviaux, Carine; Amouric, Agnes; Betzi, Stephane; Horvath, Dragos; Varnek, Alexandre; Collette, Yves; Combes, Sebastien; Roche, Philippe; Morelli, XavierJournal of Medicinal Chemistry (2018), 61 (13), 5719-5732CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chem. probes consisting of a focused-chem.-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chem. reactions carefully chosen from a list of one-step org. transformations relevant in medicinal chem. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compds. with improved affinity by several orders of magnitude.
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Abstract
Figure 1
Figure 1. Overview of recent strategic advances in medicinal chemistry.
Figure 2
Figure 2. Examples of drugs that have been repositioned: finding and developing new uses for the approved drugs.
Figure 3
Figure 3. Identifying and developing new uses from existing (investigational) drugs via new approaches or further optimization.
Figure 4
Figure 4. Representative broad-spectrum antiviral drugs.
Figure 5
Figure 5. Discovery of bioactive molecules via diversity-oriented “privileged structure” repositioning approach.
Figure 6
Figure 6. Discovery of bioactive molecules via target similarity-inspired “privileged structure” repositioning.
Figure 7
Figure 7. Discovery of highly potent and selective inhibitors through click chemistry-based combinatorial fragment assembly. CuAAC: copper(I)-catalyzed azide–alkyne [3 + 2] dipolar cycloaddition.
Figure 8
Figure 8. (A) KTGS principle. Best building blocks from each binding pocket of the biomolecule would preferentially react together because of their spatial proximity and afford the corresponding dimeric binder displaying synergistic bioactivity. (B) Thermodynamically controlled TGS or DCC principle. From appropriate fragments under equilibrium conditions, suitable dynamic combinatorial libraries (DCLs) are built up, allowing the generation of all possible library members in a thermodynamically controlled distribution (via selection pressure of the biotarget).
Figure 9
Figure 9. Kinetic target-guided synthesis of (A) cell-permeable O-GlcNAc transferase inhibitors and (B) Bcl-X(L)/BH3 protein–protein interaction modulators.
Figure 10
Figure 10. Tetrazine bioorthogonal reaction was used to form drug-like heterobifunctional molecule 87 inside cells, as the BRD4 degrader via the ubiquitin pathway.(98)
Figure 11
Figure 11. GAT1 inhibitor hits 88 and 89 were obtained by means of library screening and further optimization.
Figure 12
Figure 12. Bioorthogonally activated palladium-labile prodrug strategy and toxigenic mode of action (Prototype drugs were highlighted in blue).
Figure 13
Figure 13. Schematic illustration of the application of the highly strained alkene transcyclooctene and ene ether to mask an amine or alcohol.(109)
Figure 14
Figure 14. Photoactivatable caged kinase inhibitors, HDAC inhibitors, and photoactivatable prodrug of doxazolidine targeting exosomes. Essentially, the photo prodrug concept is based on the mask of a pharmacophoric moiety. The PPG (pink) is therefore attached to the bioactive compound by a covalent bond. The parent bioactive molecules can be released by irradiation with ultraviolet light. Therefore, this method might improve higher drug concentrations in the area of interest sparing other compartments (such as cancer-afflicted tissues) in a rapid and efficient manner with lower side effects.
Figure 15
Figure 15. Photosensitizers 107 and 108 mediated by GnRH receptors, and 109, the far-red light-activatable prodrug of PTX.
Figure 16
Figure 16. Chemical structures of phototrexate in the trans (in the dark and under blue/white light illumination) and cis (under UVA illumination) configurations.
Figure 17
Figure 17. Late-stage functionalization using C–H diversification reactions and cytochrome P450 enabled rapid identification of HDAC inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, and phosphodiesterase 2 inhibitors.
Figure 18
Figure 18. Antibody-recruiting small molecules 128 and 130 that target HIV gp120 and 131 that targets prostate-specific membrane antigen.
Figure 19
Figure 19. Examples of the in vivo noncovalent endogenous HSA targeting approach.
Figure 20
Figure 20. (A) X-ray structure of human serum albumin (bound with diflunisal, PDB ID 2BXE): the position of cysteine-34 is highlighted. (B) Schematic illustration of in vivo thiol–maleimide conjugation. (C) Chemical structure of doxorubicin-maleimide derivative 138, gemcitabine-maleimide derivatives 139 and 140, and albuvirtide.
Figure 21
Figure 21. (A) Approved AChE inhibitors for the symptomatic treatment of AD and schematic representation of the ligand binding site of AChE; the “anionic” and “esterase” sites are highlighted. (B) Rational design of central selective AChE inhibitors via a “bio-oxidizable” prodrug approach.
Figure 22
Figure 22. Mitochondria-targeted anticancer agents.
Figure 23
Figure 23. Covalent inhibitors in drug discovery: typical examples. The warheads for covalent binding are highlighted in red.
Figure 24
Figure 24. Discovery of covalent inhibitors via (A) optimization of noncovalent reversible interactions and (B) diversity-oriented modification of warheads.
Figure 25
Figure 25. Structures of boron-containing drugs.
Figure 26
Figure 26. Structure of stilbene boronic acid 175 and its binding mode with TTR (PDB code 5u4f).
Figure 27
Figure 27. Discovery of boronic acid-bearing subpicomolar inhibitors of HIV-1 protease.
Figure 28
Figure 28. Discovery of 179 as a capped peptide–boronic acid inhibitor of flaviviral proteases and its binding mode with West Nile virus NS2B-NS3 protease (PDB code 5IDK).
Figure 29
Figure 29. Cocrystal structure of 180 in complex with ADC-7 β-Lactamase (PDB code 4U0X).
Figure 30
Figure 30. Covalent small molecule inhibitors with a latent electrophile or via a proximity-driven mode.
Figure 31
Figure 31. (A) Targeting MtBPL with nucleoside-based bisubstrate adenylation inhibitors. (B) Schematic representation of the transition state of DNMT (DNMT1 and DNMT3A) catalytic site and the chemical modulation strategy. In red is depicted the methyl-donor AdoMet and its mimic 4-aminoquinazoline, in blue the deoxycytidine in the DNA and its analogues, and in pink the linker between the two moieties. Besides, the amino moiety in C4 position of the quinazoline was substituted by phenylpropylamine as a hydrophobic group on the amine at C4 position of the adenosine in AdoMet analogues, which was probably favorable for DNMT inhibition potency. (C) Discovery of a bisubstrate inhibitor of NNMT.
Figure 32
Figure 32. Structure-based optimization based on the X-ray structure of Arbidol bound to influenza virus hemagglutinin (H3-HK68: A/Hong Kong/1/1968; PDB code 5T6N).
Figure 33
Figure 33. Schematic diagram of interdisciplinary teamwork at the interface between the field of chemistry and biology with the aid of informatics.
References
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- 11Madrid, P. B.; Chopra, S.; Manger, I. D.; Gilfillan, L.; Keepers, T. R.; Shurtleff, A. C.; Green, C. E.; Iyer, L. V.; Dilks, H. H.; Davey, R. A.; Kolokoltsov, A. A.; Carrion, R., Jr.; Patterson, J. L.; Bavari, S.; Panchal, R. G.; Warren, T. K.; Wells, J. B.; Moos, W. H.; Burke, R. L.; Tanga, M. J. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One 2013, 8, e60579, DOI: 10.1371/journal.pone.0060579[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXmtlSgsrc%253D&md5=9041e9a699494765f27c68a9fcb8144eA systematic screen of FDA-approved drugs for inhibitors of biological threat agentsMadrid, Peter B.; Chopra, Sidharth; Manger, Ian D.; Gilfillan, Lynne; Keepers, Tiffany R.; Shurtleff, Amy C.; Green, Carol E.; Iyer, Lalitha V.; Hutcheson Dilks, Holli; Davey, Robert A.; Kolokoltsov, Andrey A.; Carrion, Ricardo, Jr.; Patterson, Jean L.; Bavari, Sina; Panchal, Rekha G.; Warren, Travis K.; Wells, Jay B.; Moos, Walter H.; Burke, RaeLyn L.; Tanga, Mary J.PLoS One (2013), 8 (4), e60579CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)The rapid development of effective medical countermeasures against potential biol. threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufg. and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency. A large systematic effort to det. whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biol. threat pathogens, which were validated in secondary assays. As expected, antibiotic compds. were highly active against bacterial agents, but we did not identify any non-antibiotic compds. with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compds. in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compd. identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo. The feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.
- 12Ashburn, T. T.; Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discovery 2004, 3, 673– 683, DOI: 10.1038/nrd1468[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVOhtL8%253D&md5=0145c02423ab81ace6e3b3d92585ccccDrug repositioning: identifying and developing new uses for existing drugsAshburn, Ted T.; Thor, Karl B.Nature Reviews Drug Discovery (2004), 3 (8), 673-683CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of prodn. to biotechnol. companies. More and more companies are scanning the existing pharmacopeia for repositioning candidates, and the no. of repositioning success stories is increasing.
- 13Nosengo, N. Can you teach old drugs new tricks?. Nature 2016, 534, 314– 316, DOI: 10.1038/534314a[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s7gs1ylug%253D%253D&md5=e521004f61101d4936d8e1f07454e843Can you teach old drugs new tricks?Nosengo NicolaNature (2016), 534 (7607), 314-6 ISSN:.There is no expanded citation for this reference.
- 14Hayashi, T.; Jean, M.; Huang, H.; Simpson, S.; Santoso, N. G.; Zhu, J. Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcription. Antiviral Res. 2017, 146, 76– 85, DOI: 10.1016/j.antiviral.2017.08.013[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtl2nsrzP&md5=3310d7e39f4e907dd32f1a1c39add801Screening of an FDA-approved compound library identifies levosimendan as a novel anti-HIV-1 agent that inhibits viral transcriptionHayashi, Tsuyoshi; Jean, Maxime; Huang, Huachao; Simpson, Sydney; Santoso, Netty G.; Zhu, JianAntiviral Research (2017), 146 (), 76-85CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Combination antiretroviral therapy (cART) has been proven to efficiently inhibit ongoing replication of human immunodeficiency virus type 1 (HIV-1), and significantly improve the health outcome in patients of acquired immune deficiency syndrome (AIDS). However, cART is unable to cure HIV-1/AIDS. Even in presence of cART there exists a residual viremia, contributed from the viral reservoirs of latently infected HIV-1 proviruses; this constitutes a major hurdle. Currently, there are multiple strategies aimed at eliminating or permanently silence these HIV-1 latent reservoirs being intensely explored. One such strategy, a recently emerged "block and lock" approach is appealing. For this approach, so-called HIV-1 latency-promoting agents (LPAs) are used to reinforce viral latency and to prevent the low-level or sporadic transcription of integrated HIV-1 proviruses. Although several LPAs have been reported, there is still a question of their suitability to be further developed as a safe and valid therapeutic agent for the clin. use. In this study, we aimed to identify new potential LPAs through the screening an FDA-approved compd. library. A new and promising anti-HIV-1 inhibitor, levosimendan, was identified from these screens. Levosimendan is currently used to treat heart failure in clinics, but it demonstrates strong inhibition of TNFα-induced HIV-1 reactivation in multiple cell lines of HIV-1 latency through affecting the HIV-1 Tat-LTR transcriptional axis. Furthermore, we confirmed that in primary CD4+ T cells levosimendan inhibits both the acute HIV-1 replication and the reactivation of latent HIV-1 proviruses. As a summary, our studies successfully identify levosimendan as a novel and promising anti-HIV-1 inhibitor, which should be immediately investigated in vivo given that it is already an FDA-approved drug.
- 15(a) Ren, J.; Zhao, Y.; Fry, E. E.; Stuart, D. I. Target identification and mode of action of four chemically divergent drugs against ebolavirus infection. J. Med. Chem. 2018, 61, 724– 733, DOI: 10.1021/acs.jmedchem.7b01249[ACS Full Text.], [CAS], Google Scholar15ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVaksLjN&md5=682cf8a4441bc9b04ccdaf0488632e09Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus InfectionRen, Jingshan; Zhao, Yuguang; Fry, Elizabeth E.; Stuart, David I.Journal of Medicinal Chemistry (2018), 61 (3), 724-733CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we show that four chem. divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compds. The binding consts. (Kd) detd. by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities detd. by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.(b) Zhao, Y.; Ren, J.; Harlos, K.; Jones, D. M.; Zeltina, A.; Bowden, T. A.; Padilla-Parra, S.; Fry, E. E.; Stuart, D. I. Toremifene interacts with and destabilizes the Ebola virus glycoprotein. Nature 2016, 535, 169– 172, DOI: 10.1038/nature18615[Crossref], [PubMed], [CAS], Google Scholar.15bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVOns7nF&md5=eceb89304e78acaf10097b333fb37478Toremifene interacts with and destabilizes the Ebola virus glycoproteinZhao, Yuguang; Ren, Jingshan; Harlos, Karl; Jones, Daniel M.; Zeltina, Antra; Bowden, Thomas A.; Padilla-Parra, Sergi; Fry, Elizabeth E.; Stuart, David I.Nature (London, United Kingdom) (2016), 535 (7610), 169-172CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Ebola viruses (EBOVs) are responsible for repeated outbreaks of fatal infections, including the recent deadly epidemic in West Africa. There are currently no approved therapeutic drugs or vaccines for the disease. EBOV has a membrane envelope decorated by trimers of a glycoprotein (GP, cleaved by furin to form GP1 and GP2 subunits), which is solely responsible for host cell attachment, endosomal entry and membrane fusion. GP is thus a primary target for the development of antiviral drugs. Here the authors report the first, to the knowledge, unliganded structure of EBOV GP, and high-resoln. complexes of GP with the anticancer drug toremifene and the painkiller ibuprofen. The high-resoln. apo structure gives a more complete and accurate picture of the mol., and allows conformational changes introduced by antibody and receptor binding to be deciphered. Unexpectedly, both toremifene and ibuprofen bind in a cavity between the attachment (GP1) and fusion (GP2) subunits at the entrance to a large tunnel that links with equiv. tunnels from the other monomers of the trimer at the three-fold axis. Protein-drug interactions with both GP1 and GP2 are predominately hydrophobic. Residues lining the binding site are highly conserved among filoviruses except Marburg virus (MARV), suggesting that MARV may not bind these drugs. Thermal shift assays show up to a 14° decrease in the protein melting temp. after toremifene binding, while ibuprofen has only a marginal effect and is a less potent inhibitor. These results suggest that inhibitor binding destabilizes GP and triggers premature release of GP2, thereby preventing fusion between the viral and endosome membranes. Thus, these complex structures reveal the mechanism of inhibition and may guide the development of more powerful anti-EBOV drugs.(c) Zhao, Y.; Ren, J.; Fry, E. E.; Xiao, J.; Townsend, A. R.; Stuart, D. I. Structures of Ebola virus glycoprotein complexes with tricyclic antidepressant and antipsychotic drugs. J. Med. Chem. 2018, 61, 4938– 4945, DOI: 10.1021/acs.jmedchem.8b00350[ACS Full Text], [CAS], Google Scholar15chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12htr0%253D&md5=49278d793b6fc24ad6ad4d8a67170c4eStructures of Ebola Virus Glycoprotein Complexes with Tricyclic Antidepressant and Antipsychotic DrugsZhao, Yuguang; Ren, Jingshan; Fry, Elizabeth E.; Xiao, Julia; Townsend, Alain R.; Stuart, David I.Journal of Medicinal Chemistry (2018), 61 (11), 4938-4945CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A large no. of Food and Drug Administration (FDA)-approved drugs have been found to inhibit the cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacol. targets, their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA-approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that antidepressants imipramine and clomipramine and antipsychotic drug thioridazine also directly interact with EBOV GP and det. the mode of interaction by crystallog. anal. of the complexes. The compds. bind within the same pocket as obsd. for other, chem. divergent complexes but with different binding modes. These details should be of value for the development of potent EBOV inhibitors.
- 16Zhang, L.; Wei, T. T.; Li, Y.; Li, J.; Fan, Y.; Huang, F. Q.; Cai, Y. Y.; Ma, G.; Liu, J. F.; Chen, Q. Q.; Wang, S. L.; Li, H.; Alolga, R. N.; Liu, B.; Zhao, D. S.; Shen, J. H.; Wang, X. M.; Zhu, W.; Li, P.; Qi, L. W. Functional metabolomics characterizes a key role for N-acetylneuraminic acid in coronary artery diseases. Circulation 2018, 137, 1374– 1390, DOI: 10.1161/CIRCULATIONAHA.117.031139[Crossref], [PubMed], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlvVKlt74%253D&md5=edff9fe687a87a1bace78c3b1c247217Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery DiseasesZhang, Lei; Wei, Ting-Ting; Li, Yong; Li, Jing; Fan, Yong; Huang, Feng-Qing; Cai, Yuan-Yuan; Ma, Gaoxiang; Liu, Jin-Feng; Chen, Qian-Qian; Wang, Shi-Lei; Li, Honglin; Alolga, Raphael N.; Liu, Baolin; Zhao, Dong-Sheng; Shen, Jian-Hua; Wang, Xiang-Ming; Zhu, Wei; Li, Ping; Qi, Lian-WenCirculation (2018), 137 (13), 1374-1390CODEN: CIRCAZ; ISSN:0009-7322. (Lippincott Williams & Wilkins)Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Methods: A cohort of 2324 patients who underwent coronary angiog. from 4 independent centers was studied. A combination of ultra-performance liq. chromatog. and quadrupole time-of-flight mass spectrometry in the neg. ion mode was used for untargeted anal. of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liq. chromatog.-mass spectrometry-based approach using isotope-labeled std. addn. was subsequently performed for targeted anal. of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. Results: We identified a total of 36 differential metabolites, 35 of which were confirmed with ref. compds. Elevation of Neu5Ac was obsd. in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-assocd. coiled-coil contg. protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation-induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacol. inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Conclusions: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
- 17Urquiza, P.; Laín, A.; Sanz-Parra, A.; Moreno, J.; Bernardo-Seisdedos, G.; Dubus, P.; González, E.; Gutiérrez-de-Juan, V.; García, S.; Eraña, H.; San Juan, I.; Macías, I.; Ben Bdira, F.; Pluta, P.; Ortega, G.; Oyarzábal, J.; González-Muñiz, R.; Rodríguez-Cuesta, J.; Anguita, J.; Díez, E.; Blouin, J. M.; de Verneuil, H.; Mato, J. M.; Richard, E.; Falcón-Pérez, J. M.; Castilla, J.; Millet, O. Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria. Sci. Transl. Med. 2018, 10, eaat7467, DOI: 10.1126/scitranslmed.aat7467
- 18Gwag, T.; Meng, Z.; Sui, Y.; Helsley, R. N.; Park, S. H.; Wang, S.; Greenberg, R. N.; Zhou, C. Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis. J. Hepatol. 2019, 70, 930, DOI: 10.1016/j.jhep.2018.12.038[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjt1Sqt74%253D&md5=623f1c1280d15072aa15930c5d1d2c13Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosisGwag, Taesik; Meng, Zhaojie; Sui, Yipeng; Helsley, Robert N.; Park, Se-Hyung; Wang, Shuxia; Greenberg, Richard N.; Zhou, ChangchengJournal of Hepatology (2019), 70 (5), 930-940CODEN: JOHEEC; ISSN:0168-8278. (Elsevier B.V.)The most prescribed non-nucleoside reverse transcriptase inhibitor, efavirenz, has been assocd. with elevated risk of dyslipidemia and hepatic steatosis in HIV-infected patients but the underlying mechanisms remain elusive. Herein, we investigated the role of pregnane X receptor (PXR) in mediating the adverse effects of efavirenz on lipid homeostasis.Cell-based reporter assays, primary cell culture, and multiple mouse models including conditional knockout and humanized mice were combined to study the impact of efavirenz on PXR activities and lipid homeostasis in vitro and in vivo. A novel liver-specific Pxr knockout mouse model was also generated to det. the contribution of hepatic PXR signaling to efavirenz-elicited dyslipidemia and hepatic steatosis.We found that efavirenz is a potent PXR-selective agonist that can efficiently activate PXR and induce its target gene expression in vitro and in vivo. Treatment with efavirenz-induced hypercholesterolemia and hepatic steatosis in mice but deficiency of hepatic PXR abolished these adverse effects. Interestingly, efavirenz-mediated PXR activation regulated the expression of several key hepatic lipogenic genes including fatty acid transporter CD36 and cholesterol biosynthesis enzyme squalene epoxidase (SQLE), leading to increased lipid uptake and cholesterol biosynthesis in hepatic cells. While CD36 is a known PXR target gene, we identified a DR-2-type of PXR-response element in the SQLE promoter and established SQLE as a direct transcriptional target of PXR. Since PXR exhibits considerable differences in its pharmacol. across species, we also confirmed these findings in PXR-humanized mice and human primary hepatocytes.The widely prescribed antiretroviral drug efavirenz induces hypercholesterolemia and hepatic steatosis by activating PXR signaling. Activation of PXR should be taken into consideration for patients undergoing long-term treatment with PXR agonistic antiretroviral drugs.Efavirenz is widely prescribed for HIV-infected patients but has some side effects. It can increase lipid levels in patients' blood and liver. Here we show that efavirenz can activate a unique liver protein called PXR which mediates the adverse effects of efavirenz on lipid levels in mouse models.
- 19Gkountela, S.; Castro-Giner, F.; Szczerba, B. M.; Vetter, M.; Landin, J.; Scherrer, R.; Krol, I.; Scheidmann, M. C.; Beisel, C.; Stirnimann, C. U.; Kurzeder, C.; Heinzelmann-Schwarz, V.; Rochlitz, C.; Weber, W. P.; Aceto, N. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell 2019, 176, 98– 112, DOI: 10.1016/j.cell.2018.11.046[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXovFyqtw%253D%253D&md5=5a284c121841c562245da2948b8a4dedCirculating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis SeedingGkountela, Sofia; Castro-Giner, Francesc; Szczerba, Barbara Maria; Vetter, Marcus; Landin, Julia; Scherrer, Ramona; Krol, Ilona; Scheidmann, Manuel C.; Beisel, Christian; Stirnimann, Christian U.; Kurzeder, Christian; Heinzelmann-Schwarz, Viola; Rochlitz, Christoph; Weber, Walter Paul; Aceto, NicolaCell (Cambridge, MA, United States) (2019), 176 (1-2), 98-112.e14CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biol. features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-assocd. transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biol. Among 2,486 FDA-approved compds., we identify Na+/K+ ATPase inhibitors that enable the dissocn. of CTC clusters into single cells, leading to DNA methylation remodeling at crit. sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compds. to suppress the spread of cancer.
- 20Marrugal-Lorenzo, J. A.; Serna-Gallego, A.; Berastegui-Cabrera, J.; Pachón, J.; Sánchez-Céspedes, J. Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections. Sci. Rep. 2019, 9, 17, DOI: 10.1038/s41598-018-37290-3[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnpsl2gtQ%253D%253D&md5=39abad14b67924960bbec0203507c94bRepositioning salicylanilide anthelmintic drugs to treat adenovirus infectionsMarrugal-Lorenzo Jose A; Serna-Gallego Ana; Berastegui-Cabrera Judith; Pachon Jeronimo; Sanchez-Cespedes Javier; Pachon Jeronimo; Sanchez-Cespedes JavierScientific reports (2019), 9 (1), 17 ISSN:.The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia.
- 21Liu, Z.; Fang, H.; Reagan, K.; Xu, X.; Mendrick, D. L.; Slikker, W., Jr.; Tong, W. In silico drug repositioning: what we need to know. Drug Discovery Today 2013, 18, 110– 115, DOI: 10.1016/j.drudis.2012.08.005[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlGnsL3J&md5=3a5c533b306e3fed00b49285efff3a33In silico drug repositioning - what we need to knowLiu, Zhichao; Fang, Hong; Reagan, Kelly; Xu, Xiaowei; Mendrick, Donna L.; Slikker, William; Tong, WeidaDrug Discovery Today (2013), 18 (3-4), 110-115CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs. Recent research has shown that bioinformatics-based approaches have the potential to offer systematic insights into the complex relationships among drugs, targets and diseases necessary for successful repositioning. In this article, we propose the key bioinformatics steps essential for discovering valuable repositioning methods. The proposed steps (repurposing with a purpose, repurposing with a strategy and repurposing with confidence) are aimed at providing a repurposing pipeline, with particular focus on the proposed Drugs of New Indications (DNI) database, which can be used alongside currently available resources to improve in silico drug repositioning.
- 22Haupt, V. J.; Schroeder, M. Old friends in new guise: repositioning of known drugs with structural bioinformatics. Briefings Bioinf. 2011, 12, 312– 326, DOI: 10.1093/bib/bbr011[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptl2jsrc%253D&md5=e50e0f4752302d91263af4803ef0f14dOld friends in new guise: repositioning of known drugs with structural bioinformaticsHaupt, V. Joachim; Schroeder, MichaelBriefings in Bioinformatics (2011), 12 (4), 312-326CODEN: BBIMFX; ISSN:1467-5463. (Oxford University Press)A review. Developing a drug de novo is a laborious and costly endeavor. Thus, the repositioning of already approved drugs for the treatment of new diseases is promising and valuable. One computational approach to repositioning exploits the structural similarity of binding sites of known and new targets. Here, we review computational methods to represent and align binding sites. We review available tools, present success stories and discuss limits of the approach.
- 23McClure, R. A.; Williams, J. D. Impact of mass spectrometry-based technologies and strategies on chemoproteomics as a tool for drug discovery. ACS Med. Chem. Lett. 2018, 9, 785– 791, DOI: 10.1021/acsmedchemlett.8b00181[ACS Full Text], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXht1Kns7fO&md5=2db5a5a100646e41ac01bef8318bc7e4Impact of Mass Spectrometry-Based Technologies and Strategies on Chemoproteomics as a Tool for Drug DiscoveryMcClure, Ryan A.; Williams, Jon D.ACS Medicinal Chemistry Letters (2018), 9 (8), 785-791CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Chemoproteomics is an invaluable tool to discover protein targets from phenotypic assays and to understand on- and off-target engagement of potential therapeutic compds. Highlighted in this technol. perspective is our view on how improvements in mass spectrometry (MS)-based proteomics technol. have dramatically impacted chemoproteomics. Improvements in sample prepn., MS instrumentation, data acquisition, and quantification strategies have enabled medicinal chemists, chem. biologists, and mass spectrometrists to develop new chemoproteomic expts. and improve existing methods. As a result of improvements in MS, we will detail how bead-based affinity capture and activity-based proteome profiling methods have been reduced from multiple LC-MS runs for samples and controls down to a single LC-MS run each for sample and control. With improvements in scan duty cycle and sensitivity, sufficient depth of proteome coverage can be obtained for capture-free methods, which do not utilize an enrichment step.
- 24Lim, R. K.; Lin, Q. Photoinducible bioorthogonal chemistry: a spatiotemporally controllable tool to visualize and perturb proteins in live cells. Acc. Chem. Res. 2011, 44, 828– 839, DOI: 10.1021/ar200021p[ACS Full Text], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmtlylt70%253D&md5=454ee044eca81c414f5f72118012ad28Photoinducible Bioorthogonal Chemistry: A Spatiotemporally Controllable Tool to Visualize and Perturb Proteins in Live CellsLim, Reyna K. V.; Lin, QingAccounts of Chemical Research (2011), 44 (9), 828-839CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)A review. Visualization in biol. has been greatly facilitated by the use of fluorescent proteins as in-cell probes. The genes coding for these wavelength-tunable proteins can be readily fused with the DNA coding for a protein of interest, which enables direct monitoring of natural proteins in real time inside living cells. Despite their success, however, fluorescent proteins have limitations that have only begun to be addressed in the past decade through the development of bioorthogonal chem. In this approach, a very small bioorthogonal tag is embedded within the basic building blocks of the cell, and then a variety of external mols. can be selectively conjugated to these pretagged biomols. The result is a veritable palette of biophys. probes for the researcher to choose from. In this Account, the authors review their progress in developing a photoinducible, bioorthogonal tetrazole-alkene cycloaddn. reaction ("photoclick chem.") and applying it to probe protein dynamics and function in live cells. The work described here summarizes the synthesis, structure, and reactivity studies of tetrazoles, including their optimization for applications in biol. Building on key insights from earlier reports, the authors' initial studies of the reaction have revealed full water compatibility, high photoactivation quantum yield, tunable photoactivation wavelength, and broad substrate scope; an added benefit is the formation of fluorescent cycloadducts. Subsequent studies have shown fast reaction kinetics (up to 11.0 M-1 s-1), with the rate depending on the HOMO energy of the nitrile imine dipole as well as the LUMO energy of the alkene dipolarophile. Moreover, through the use of photocrystallog., the authors have obsd. that the photogenerated nitrile imine adopts a bent geometry in the solid state. This observation has led to the synthesis of reactive, macrocyclic tetrazoles that contain a short "bridge" between two flanking Ph rings. This photoclick chem. has been used to label proteins rapidly (within ∼1 min) both in vitro and in Escherichia coli. To create an effective interface with biol., the authors have identified both a metabolically incorporable alkene amino acid, homoallylglycine, and a genetically encodable tetrazole amino acid, p-(2-tetrazole)phenylalanine. The authors demonstrate the utility of these two moieties, resp., in spatiotemporally controlled imaging of newly synthesized proteins and in site-specific labeling of proteins. Addnl., the authors demonstrate the use of the photoclick chem. to perturb the localization of a fluorescent protein in mammalian cells.
- 25Head, S. A.; Liu, J. O. Identification of small molecule-binding proteins in a native cellular environment by live-cell photoaffinity labeling. J. Vis. Exp. 2016, 115, e54529, DOI: 10.3791/54529
- 26Hill, J. R.; Robertson, A. A. B. Fishing for drug targets: a focus on diazirine photoaffinity probe synthesis. J. Med. Chem. 2018, 61, 6945– 6963, DOI: 10.1021/acs.jmedchem.7b01561[ACS Full Text], [CAS], Google Scholar26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotFart7g%253D&md5=37266e26bdd6a2028dddffc3ead4390dFishing for Drug Targets: A Focus on Diazirine Photoaffinity Probe SynthesisHill, James R.; Robertson, Avril A. B.Journal of Medicinal Chemistry (2018), 61 (16), 6945-6963CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Target identification is a high-priority, albeit challenging, aspect of drug discovery. Diazirine-based photoaffinity probes (PAPs) can facilitate the process by covalently capturing transient mol. interactions. This can help identify target proteins and map the ligand's interactome. Diazirine probes have even been incorporated by cellular machinery into proteins. Embarking on the synthesis of customized PAPs, contg. either an aliph. or trifluoromethyl Ph diazirine, can be a considerable endeavor, particularly for medicinal chemists and chem. biologists new to the field. This review takes a synthetic focus, aiming to summarize available routes, propose new avenues, and illuminate recent advances in diazirine synthesis. Select examples of diazirine photoaffinity labeling applications have been included throughout to provide instructive definition of the advantages and limitations of the technol. while simultaneously highlighting how these reagents can be applied in a practical sense.
- 27Hu, Y.; Wassermann, A. M.; Lounkine, E.; Bajorath, J. Systematic analysis of public domain compound potency data identifies selective molecular scaffolds across druggable target families. J. Med. Chem. 2010, 53, 752– 758, DOI: 10.1021/jm9014229[ACS Full Text], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsFekt7%252FL&md5=aaf07367ea08bc6f49e29e94ae9bb231Systematic Analysis of Public Domain Compound Potency Data Identifies Selective Molecular Scaffolds across Druggable Target FamiliesHu, Ye; Wassermann, Anne Mai; Lounkine, Eugen; Bajorath, JuergenJournal of Medicinal Chemistry (2010), 53 (2), 752-758CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mol. scaffolds that yield target family-selective compds. are of high interest in pharmaceutical research. There continues to be considerable debate in the field as to whether chemotypes with a priority selectivity for given target families and/or targets exist and how they might be identified. What do currently available data tell us. We present a systematic and comprehensive selectivity-centric anal. of public domain target-ligand interactions. More than 200 mol. scaffolds are identified in currently available active compds. that are selective for established target families. A subset of these scaffolds is found to produce compds. with high selectivity for individual targets among closely related ones. These scaffolds are currently underrepresented in approved drugs.
- 28Ma, D. L.; Chan, D. S.; Leung, C. H. Drug repositioning by structure-based virtual screening. Chem. Soc. Rev. 2013, 42, 2130– 2141, DOI: 10.1039/c2cs35357a[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXit1Grsbo%253D&md5=8f419390fe9ac04b6e63ec17d91df471Drug repositioning by structure-based virtual screeningMa, Dik-Lung; Chan, Daniel Shiu-Hin; Leung, Chung-HangChemical Society Reviews (2013), 42 (5), 2130-2141CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. Approved drugs have favorable or validated pharmacokinetic properties and toxicol. profiles, and the repositioning of existing drugs for new indications can potentially avoid expensive costs assocd. with early-stage testing of the hit compds. In recent years, technol. advances in virtual screening methodologies have allowed medicinal chemists to rapidly screen drug libraries for therapeutic activity against new biomol. targets in a cost-effective manner. This review article outlines the basic principles and recent advances in structure-based virtual screening and highlights the powerful synergy of in silico techniques in drug repositioning as demonstrated in several recent reports.
- 29Giannopoulos, P. F.; Chiu, J.; Pratico, D. Learning impairments, memory deficits, and neuropathology in aged tau transgenic mice are dependent on leukotrienes biosynthesis: role of the cdk5 kinase pathway. Mol. Neurobiol. 2019, 56, 1211, DOI: 10.1007/s12035-018-1124-7[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSmtrzP&md5=9c3b36329819f656295c22f847de5889Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase PathwayGiannopoulos, Phillip F.; Chiu, Jian; Pratico, DomenicoMolecular Neurobiology (2019), 56 (2), 1211-1220CODEN: MONBEW; ISSN:0893-7648. (Humana Press Inc.)Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathol. phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathol. have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 mo of age for 16 wk and then assessed in their functional and pathol. phenotype. Compared with baseline, we obsd. that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant redn. in tau phosphorylation and pathol., which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathol. phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.
- 30Lu, W.; Yao, X.; Ouyang, P.; Dong, N.; Wu, D.; Jiang, X.; Wu, Z.; Zhang, C.; Xu, Z.; Tang, Y. Drug repurposing of histone deacetylase inhibitors that alleviate neutrophilic inflammation in acute lung injury and idiopathic pulmonary fibrosis via inhibiting leukotriene A4 hydrolase and blocking LTB4 biosynthesis. J. Med. Chem. 2017, 60, 1817– 1828, DOI: 10.1021/acs.jmedchem.6b01507[ACS Full Text], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtVWqurk%253D&md5=a94045bbbe5514eb48b1468b54cac0b5Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 BiosynthesisLu, Weiqiang; Yao, Xue; Ouyang, Ping; Dong, Ningning; Wu, Dang; Jiang, Xingwu; Wu, Zengrui; Zhang, Chen; Xu, Zhongyu; Tang, Yun; Zou, Shien; Liu, Mingyao; Li, Jian; Zeng, Minghua; Lin, Ping; Cheng, Feixiong; Huang, JinJournal of Medicinal Chemistry (2017), 60 (5), 1817-1828CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, the authors identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analog 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymic assay, thermofluor assay, and x-ray Crystallog. investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clin. safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were detd. in vivo. Collectively, 1 and 2 would provide promising agents with well-known clin. safety for potential treatment in patients with ALI and IPF via pharmacol. inhibiting LAT4H and blocking LTB4 biosynthesis.
- 31Iwata, M.; Hirose, L.; Kohara, H.; Liao, J.; Sawada, R.; Akiyoshi, S.; Tani, K.; Yamanishi, Y. Pathway-based drug repositioning for cancers: computational prediction and experimental validation. J. Med. Chem. 2018, 61, 9583– 9595, DOI: 10.1021/acs.jmedchem.8b01044[ACS Full Text], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVWit7fN&md5=ebdf14f917554fff73592cbb2e7c10f8Pathway-Based Drug Repositioning for Cancers: Computational Prediction and Experimental ValidationIwata, Michio; Hirose, Lisa; Kohara, Hiroshi; Liao, Jiyuan; Sawada, Ryusuke; Akiyoshi, Sayaka; Tani, Kenzaburo; Yamanishi, YoshihiroJournal of Medicinal Chemistry (2018), 61 (21), 9583-9595CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use mol. pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chem. induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and exptl. validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.
- 32Mejía-Pedroza, R. A.; Espinal-Enríquez, J.; Hernández-Lemus, E. Pathway-based drug repositioning for breast cancer molecular subtypes. Front Pharmacol. 2018, 9, 905, DOI: 10.3389/fphar.2018.00905[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtVaqsrs%253D&md5=51adc21df40b93cac9c088583436f4c1Pathway-based drug repositioning for breast cancer molecular subtypesMejia-Pedroza, Raul A.; Espinal-Enriquez, Jesus; Hernandez-Lemus, EnriqueFrontiers in Pharmacology (2018), 9 (), 905/1-905/13CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)Breast cancer is a major public health problem which treatment needs new pharmacol. options. In the last decades, during the postgenomic era new theor. and technol. tools that give us novel and promising ways to address these problems have emerged. In this work, we integrate several tools that exploit disease-specific exptl. transcriptomic results in addn. to information from biol. and pharmacol. data bases obtaining a contextual prioritization of pathways and drugs in breast cancer subtypes. The usefulness of these results should be evaluated in terms of drug repurposing in each breast cancer mol. subtype therapy. In favor of breast cancer patients, this methodol. could be further developed to provide personalized treatment schemes. The latter are particularly needed in those breast cancer subtypes with limited therapeutic options or those who have developed resistance to the current pharmacol. schemes.
- 33Huang, C. H.; Chang, P. M.; Lin, Y. J.; Wang, C. H.; Huang, C. Y.; Ng, K. L. Drug repositioning discovery for early- and late-stage non-small-cell lung cancer. Biomed Res. Int. 2014, 2014, 193817, DOI: 10.1155/2014/193817[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M7gsVWqtQ%253D%253D&md5=2e0c6fbc90b3ccac729ace9759901d72Drug repositioning discovery for early- and late-stage non-small-cell lung cancerHuang Chien-Hung; Lin Yong-Jie; Chang Peter Mu-Hsin; Wang Cheng-Hsu; Huang Chi-Ying F; Ng Ka-LokBioMed research international (2014), 2014 (), 193817 ISSN:.Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC) is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.
- 34Astolfi, A.; Felicetti, T.; Iraci, N.; Manfroni, G.; Massari, S.; Pietrella, D.; Tabarrini, O.; Kaatz, G. W.; Barreca, M. L.; Sabatini, S.; Cecchetti, V. Pharmacophore-based repositioning of approved drugs as novel staphylococcus aureus NorA efflux pump inhibitors. J. Med. Chem. 2017, 60, 1598– 1604, DOI: 10.1021/acs.jmedchem.6b01439[ACS Full Text], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFajsbY%253D&md5=6936777b99a9832f2582c22c9492bc1dPharmacophore-Based Repositioning of Approved Drugs as Novel Staphylococcus aureus NorA Efflux Pump InhibitorsAstolfi, Andrea; Felicetti, Tommaso; Iraci, Nunzio; Manfroni, Giuseppe; Massari, Serena; Pietrella, Donatella; Tabarrini, Oriana; Kaatz, Glenn W.; Barreca, Maria L.; Sabatini, Stefano; Cecchetti, ViolettaJournal of Medicinal Chemistry (2017), 60 (4), 1598-1604CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An intriguing opportunity to address antimicrobial resistance is represented by the inhibition of efflux pumps. Focusing on NorA, the most important efflux pump of Staphylococcus aureus, an efflux pump inhibitors (EPIs) library was used for ligand-based pharmacophore modeling studies. Exploiting the obtained models, an in silico drug repositioning approach allowed for the identification of novel and potent NorA EPIs.
- 35Fako, V. E.; Wu, X.; Pflug, B.; Liu, J. Y.; Zhang, J. T. Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase. J. Med. Chem. 2015, 58, 778– 784, DOI: 10.1021/jm501543u[ACS Full Text], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOhu7%252FN&md5=33e2aa65f5a5b4fd5f14df6e618982edRepositioning Proton Pump Inhibitors as Anticancer Drugs by Targeting the Thioesterase Domain of Human Fatty Acid SynthaseFako, Valerie E.; Wu, Xi; Pflug, Beth; Liu, Jing-Yuan; Zhang, Jian-TingJournal of Medicinal Chemistry (2015), 58 (2), 778-784CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clin. use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compds. may be acting on cancer cells.
- 36(a) Li, H.; Liu, A.; Zhao, Z.; Xu, Y.; Lin, J.; Jou, D.; Li, C. Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J. Med. Chem. 2011, 54, 5592– 5596, DOI: 10.1021/jm101330h[ACS Full Text.], [CAS], Google Scholar36ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXosFykurs%253D&md5=eab2abdff8c67119767b0c147920ad4cFragment-Based Drug Design and Drug Repositioning Using Multiple Ligand Simultaneous Docking (MLSD): Identifying Celecoxib and Template Compounds as Novel Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3)Li, Huameng; Liu, Aiguo; Zhao, Zhenjiang; Xu, Yufang; Lin, Jiayuh; Jou, David; Li, ChenglongJournal of Medicinal Chemistry (2011), 54 (15), 5592-5596CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors describe a novel method of drug discovery using MLSD and drug repositioning, with cancer target STAT3 being used as a test case. Multiple drug scaffolds were simultaneously docked into hot spots of STAT3 by MLSD, followed by tethering to generate virtual template compds. Similarity search of virtual hits on drug database identified celecoxib as a novel inhibitor of STAT3. Furthermore, the authors designed two novel lead inhibitors based on one of the lead templates and celecoxib.(b) Li, H.; Xiao, H.; Lin, L.; Jou, D.; Kumari, V.; Lin, J.; Li, C. Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J. Med. Chem. 2014, 57, 632– 641, DOI: 10.1021/jm401144z[ACS Full Text], [CAS], Google Scholar36bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXht1Ohtr8%253D&md5=a4f2887c2ad3a5dc97827e7a7499efe0Drug Design Targeting Protein-Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 InterfaceLi, Huameng; Xiao, Hui; Lin, Li; Jou, David; Kumari, Vandana; Lin, Jiayuh; Li, ChenglongJournal of Medicinal Chemistry (2014), 57 (3), 632-641CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The IL-6/GP130/STAT3 pathway is crit. for the progression of multiple types of cancers. The authors report the discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into hot spots of GP130 D1 domain by MLSD to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compds. Similarity searches of virtual hits on drug databases identified raloxifene and bazedoxifene as potential inhibitors of IL-6/GP130 interaction. In cancer cell assays both compds. bind to GP130 and demonstrated selective inhibition of IL-6 induced STAT3 phosphorylation and were significantly more potent than the previously reported natural product inhibitor MDL-A. The identified drugs represent a new class of lead compds. with piperidine, benzothiophene, and indole scaffolds to inhibit IL-6 induced homodimerization of GP130. Besides potential direct usage for clinic trials, the two compds. can also serve as lead compds. for optimization to speed the development of drugs selectively targeting the IL-6/GP130/STAT3 cancer signaling pathway.
- 37Vegner, L.; Peragovics, A.; Tombor, L.; Jelinek, B.; Czobor, P.; Bender, A.; Simon, Z.; Malnasi-Csizmadia, A. Experimental confirmation of new drug-target interactions predicted by drug profile matching. J. Med. Chem. 2013, 56, 8377– 8388, DOI: 10.1021/jm400813y[ACS Full Text], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFGrsr7I&md5=7790bed590d1d57b3a633ddf211ca5aaExperimental Confirmation of New Drug-Target Interactions Predicted by Drug Profile MatchingVegner, Laszlo; Peragovics, Agnes; Tombor, Laszlo; Jelinek, Balazs; Czobor, Pal; Bender, Andreas; Simon, Zoltan; Malnasi-Csizmadia, AndrasJournal of Medicinal Chemistry (2013), 56 (21), 8377-8388CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quant. predict the complete effect profiles of compds. via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature anal. as well as exptl. A total of 72% of the newly predicted and tested dopaminergic compds. were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, resp. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory consts. (Ki) were detd. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
- 38Huang, C. H.; Chang, P. M.; Hsu, C. W.; Huang, C. Y.; Ng, K. L. Drug repositioning for non-small cell lung cancer by using machine learning algorithms and topological graph theory. BMC Bioinformatics 2016, 17, S2, DOI: 10.1186/s12859-015-0845-0[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXltFeksA%253D%253D&md5=43fc74bd2590159623167ed695a74accDrug repositioning for non-small cell lung cancer by using machine learning algorithms and topological graph theoryHuang, Chien-Hung; Chang, Peter Mu-Hsin; Hsu, Chia-Wei; Huang, Chi-Ying F.; Ng, Ka-LokBMC Bioinformatics (2016), 17 (Suppl.1), 2/1-2/14CODEN: BBMIC4; ISSN:1471-2105. (BioMed Central Ltd.)Background: Non-small cell lung cancer (NSCLC) is one of the leading causes of death globally, and research into NSCLC has been accumulating steadily over several years. Drug repositioning is the current trend in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development process of drugs, as well as reducing side effects. Results: This work integrates two approaches - machine learning algorithms and topol. parameter-based classification - to develop a novel pipeline of drug repositioning to analyze four lung cancer microarray datasets, enriched biol. processes, potential therapeutic drugs and targeted genes for NSCLC treatments. A total of 7 (8) and 11 (12) promising drugs (targeted genes) were discovered for treating early- and late-stage NSCLC, resp. The effectiveness of these drugs is supported by the literature, exptl. detd. in-vitro IC50 and clin. trials. This work provides better drug prediction accuracy than competitive research according to IC50 measurements. Conclusions: With the novel pipeline of drug repositioning, the discovery of enriched pathways and potential drugs related to NSCLC can provide insight into the key regulators of tumorigenesis and the treatment of NSCLC. Based on the verified effectiveness of the targeted drugs predicted by this pipeline, we suggest that our drug-finding pipeline is effective for repositioning drugs.
- 39Dakshanamurthy, S.; Issa, N. T.; Assefnia, S.; Seshasayee, A.; Peters, O. J.; Madhavan, S.; Uren, A.; Brown, M. L.; Byers, S. W. Predicting new indications for approved drugs using a proteochemometric method. J. Med. Chem. 2012, 55, 6832– 6848, DOI: 10.1021/jm300576q[ACS Full Text], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVWhtL3K&md5=a7f3c746f47ae9370aa0d9faccd1f1bdPredicting New Indications for Approved Drugs Using a Proteochemometric MethodDakshanamurthy, Sivanesan; Issa, Naiem T.; Assefnia, Shahin; Seshasayee, Ashwini; Peters, Oakland J.; Madhavan, Subha; Uren, Aykut; Brown, Milton L.; Byers, Stephen W.Journal of Medicinal Chemistry (2012), 55 (15), 6832-6848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chem. screening, transcriptome matching, or simple in silico ligand docking. We now describe a novel rapid computational proteochemometric method called "train, match, fit, streamline" (TMFS) to map new drug-target interaction space and predict new uses. The TMFS method combines shape, topol., and chem. signatures, including docking score and functional contact points of the ligand, to predict potential drug-target interactions with remarkable accuracy. Using the TMFS method, we performed extensive mol. fit computations on 3671 FDA approved drugs across 2335 human protein crystal structures. The TMFS method predicts drug-target assocns. with 91% accuracy for the majority of drugs. Over 58% of the known best ligands for each target were correctly predicted as top ranked, followed by 66%, 76%, 84%, and 91% for agents ranked in the top 10, 20, 30, and 40, resp., out of all 3671 drugs. Drugs ranked in the top 1-40 that have not been exptl. validated for a particular target now become candidates for repositioning. Furthermore, we used the TMFS method to discover that mebendazole, an antiparasitic with recently discovered and unexpected anticancer properties, has the structural potential to inhibit VEGFR2. We confirmed exptl. that mebendazole inhibits VEGFR2 kinase activity and angiogenesis at doses comparable with its known effects on hookworm. TMFS also predicted, and was confirmed with surface plasmon resonance, that di-Me celecoxib and the anti-inflammatory agent celecoxib can bind cadherin-11, an adhesion mol. important in rheumatoid arthritis and poor prognosis malignancies for which no targeted therapies exist. We anticipate that expanding our TMFS method to the >27 000 clin. active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets.
- 40Coley, C. W.; Green, W. H.; Jensen, K. F. Machine learning in computer-aided synthesis planning. Acc. Chem. Res. 2018, 51, 1281– 1289, DOI: 10.1021/acs.accounts.8b00087[ACS Full Text], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFKhsb0%253D&md5=a1ea72c55942f3c0f0a99ab080f96899Machine Learning in Computer-Aided Synthesis PlanningColey, Connor W.; Green, William H.; Jensen, Klavs F.Accounts of Chemical Research (2018), 51 (5), 1281-1289CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small mol. compds. The ideal CASP program would take a mol. structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chem. feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two crit. aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target mol. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing no. of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chem. reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of exptl. success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network-based approaches that we and others have developed for this forward prediction task that can be trained on previously published exptl. data. Machine learning and artificial intelligence have revolutionized a no. of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure-activity models in chem., it is only now that it is being successfully applied more broadly to org. synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large.
- 41Zhong, F.; Xing, J.; Li, X.; Liu, X.; Fu, Z.; Xiong, Z.; Lu, D.; Wu, X.; Zhao, J.; Tan, X.; Li, F.; Luo, X.; Li, Z.; Chen, K.; Zheng, M.; Jiang, H. Artificial intelligence in drug design. Sci. China: Life Sci. 2018, 61, 1191, DOI: 10.1007/s11427-018-9342-2[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7ivVemsw%253D%253D&md5=bc9be49e1b60b815eed9494cd7d174c5Artificial intelligence in drug designZhong Feisheng; Xing Jing; Li Xutong; Liu Xiaohong; Fu Zunyun; Xiong Zhaoping; Lu Dong; Wu Xiaolong; Zhao Jihui; Tan Xiaoqin; Li Fei; Luo Xiaomin; Chen Kaixian; Zheng Mingyue; Jiang Hualiang; Zhong Feisheng; Xing Jing; Li Xutong; Fu Zunyun; Lu Dong; Wu Xiaolong; Zhao Jihui; Tan Xiaoqin; Liu Xiaohong; Xiong Zhaoping; Chen Kaixian; Jiang Hualiang; Li Fei; Li ZhaojunScience China. Life sciences (2018), 61 (10), 1191-1204 ISSN:.Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology, the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical trials. Owing to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence (AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening, activity scoring, quantitative structure-activity relationship (QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability, deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules, which will further promote the application of AI technologies in the field of drug design.
- 42Polamreddy, P.; Gattu, N. The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions. Drug Discovery Today 2019, 24, 789, DOI: 10.1016/j.drudis.2018.11.022[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crosVOjug%253D%253D&md5=c3fe65336ec6d598fd2f933d0174f6d6The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutionsPolamreddy Prasanthi; Gattu NanduDrug discovery today (2019), 24 (3), 789-795 ISSN:.As the name suggests, drug repurposing is a strategy to identify new therapeutic uses for marketed drugs, discontinued and/or shelved drugs, and drug candidates currently in clinical development. Although not a recent concept, drug repurposing has gained momentum over the past few years and several drugs have been successfully repurposed. Here, we summarize the drug repurposing landscape from 2012 to 2017, with a major focus on repurposed drugs, collaborative opportunities, and funding opportunities specific to drug repurposing projects. Along with success stories, we also highlight the challenges and limitations associated with drug repurposing.
- 43(a) Bartolini, S.; Mai, A.; Artico, M.; Paesano, N.; Rotili, D.; Spadafora, C.; Sbardella, G. 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones antagonize cell proliferation and induce cell differentiation by inhibiting (a nontelomeric) endogenous reverse transcriptase. J. Med. Chem. 2005, 48, 6776– 6778, DOI: 10.1021/jm0507330[ACS Full Text.], [CAS], Google Scholar43ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVGqsrrO&md5=bed817e48bba30e296dabc536e156b516-[1-(2,6-Difluorophenyl)ethyl]pyrimidinones Antagonize Cell Proliferation and Induce Cell Differentiation by Inhibiting (a Nontelomeric) Endogenous Reverse TranscriptaseBartolini, Sara; Mai, Antonello; Artico, Marino; Paesano, Nicola; Rotili, Dante; Spadafora, Corrado; Sbardella, GianlucaJournal of Medicinal Chemistry (2005), 48 (22), 6776-6778CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two 2,6-difluoro-DABO derivs. (MC 1047, 1, and MC 1220, 2, resp.) were tested against endogenous, nontelomeric reverse transcriptase (endo-RT) in human differentiating cell systems to investigate their antiproliferative and cytodifferentiating activity. The two compds. significantly reduced cell proliferation and facilitated the morphol. differentiation of cells. These results propose F2-DABOs as useful tools in preventive and/or curative therapy to counteract the loss of differentiation in dedifferentiating pathologies and as antiproliferative drugs in tumor therapy.(b) Sbardella, G.; Mai, A.; Bartolini, S.; Castellano, S.; Cirilli, R.; Rotili, D.; Milite, C.; Santoriello, M.; Orlando, S.; Sciamanna, I.; Serafino, A.; Lavia, P.; Spadafora, C. Modulation of cell differentiation, proliferation, and tumor growth by dihydrobenzyloxopyrimidine non-nucleoside reverse transcriptase inhibitors. J. Med. Chem. 2011, 54, 5927– 5936, DOI: 10.1021/jm200734j[ACS Full Text], [CAS], Google Scholar43bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXptlSmsb4%253D&md5=28a907965efda96d77ba50dbd69dd691Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase InhibitorsSbardella, Gianluca; Mai, Antonello; Bartolini, Sara; Castellano, Sabrina; Cirilli, Roberto; Rotili, Dante; Milite, Ciro; Santoriello, Marisabella; Orlando, Serena; Sciamanna, Ilaria; Serafino, Annalucia; Lavia, Patrizia; Spadafora, CorradoJournal of Medicinal Chemistry (2011), 54 (16), 5927-5936CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivs. (3a-h) belonging to the F2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compds., the most potent is 3g (SPV122), which also induces apoptosis in a cell-d.-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.
- 44Shahinas, D.; Liang, M.; Datti, A.; Pillai, D. R. A repurposing strategy identifies novel synergistic inhibitors of plasmodium falciparum heat shock protein 90. J. Med. Chem. 2010, 53, 3552– 3557, DOI: 10.1021/jm901796s[ACS Full Text], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvFKjtLg%253D&md5=e71807df99016cdaab2d338080162f11A Repurposing Strategy Identifies Novel Synergistic Inhibitors of Plasmodium falciparum Heat Shock Protein 90Shahinas, Dea; Liang, Michael; Datti, Alessandro; Pillai, Dylan R.Journal of Medicinal Chemistry (2010), 53 (9), 3552-3557CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Malaria is responsible for 3 million deaths annually. Antimalarial drug resistance is widespread, and few novel, well-defined targets exist. A robotic high throughput screen (HTS) was performed using 4000 small mols. from a natural compd. (Spectrum), pharmacol. active (Lopac), and Food and Drug Administration (FDA) approved drug library (Prestwick) for competitive inhibition of the ATP-binding (GHKL) domain of Plasmodium falciparum (Pf) Hsp90, a highly conserved chaperone. Hits were further screened for specificity based on differential inhibition of PfHsp90 in comparison to human (Hs) Hsp90. PfHsp90-specific inhibitors showed 50% inhibitory concns. (IC50) in the nanomolar range when tested using a cell-based antimalarial validation assay. Three hits, identified as selective PfHsp90 inhibitors in the HTS, also demonstrated synergistic activity in the presence of the known antimalarial drug chloroquine. These data support PfHsp90 as a specific antimalarial target with potential for synergy with known antimalarials.
- 45Deeks, E. D. Lesinurad: a review in hyperuricaemia of gout. Drugs Aging 2017, 34, 401– 410, DOI: 10.1007/s40266-017-0461-y[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmsFGjs7w%253D&md5=82a18964b609bc9da3909f715fd35c67Lesinurad: A Review in Hyperuricaemia of GoutDeeks, Emma D.Drugs & Aging (2017), 34 (5), 401-410CODEN: DRAGE6; ISSN:1170-229X. (Springer International Publishing AG)Lesinurad (Zurampic) is an oral selective inhibitor of the URAT1 and OAT4 uric acid (UA) transporters of the kidney, via which it inhibits UA reabsorption and thus increases renal UA excretion and lowers serum UA (sUA) levels. Lesinurad 200 mg once daily is indicated for use in combination with a xanthine oxidase inhibitor (XOI) to treat hyperuricemia in adults with gout who have not achieved target sUA levels with an XOI alone. Approval was based on three 12-mo phase 3 trials that evaluated lesinurad in combination with allopurinol in adults with gout inadequately responsive to allopurinol (CLEAR 1 and 2) and in combination with febuxostat in adults with tophaceous gout (CRYSTAL). The target sUA level of <6 mg/dL at 6 mo (primary endpoint) was achieved by significantly more lesinurad plus allopurinol than placebo plus allopurinol recipients in the CLEAR trials. In CRYSTAL (which enrolled patients regardless of prior XOI experience, and included 3 wk of febuxostat before randomization), the proportion of patients who achieved an sUA target of <5 mg/dL did not reach statistical significance between lesinurad plus febuxostat and placebo plus febuxostat at 6 mo (primary endpoint), although significantly favored the lesinurad plus febuxostat group at 12 mo. Notably, the sUA target of <5 mg/dL at 6 mo was met with lesinurad plus febuxostat in the CRYSTAL subgroup that had uncontrolled hyperuricemia at baseline, despite having received febuxostat pre-randomization. Lesinurad plus XOI regimens were generally not assocd. with improvements in flares and tophi in these trials, although clin. benefit became more apparent in 12-mo extension studies; the regimens were also generally well tolerated. Thus, lesinurad, in combination with an XOI, is an emerging option for the treatment of hyperuricemia in adults with gout who have not achieved target sUA levels with an XOI alone.
- 46Hoy, S. M. Lesinurad: first global approval. Drugs 2016, 76, 509– 516, DOI: 10.1007/s40265-016-0550-y[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XisFGrsr4%253D&md5=adff81ec4e67f65711573f15444765c8Lesinurad: First Global ApprovalHoy, Sheridan M.Drugs (2016), 76 (4), 509-516CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)Lesinurad (ZURAMPIC) is an oral urate-anion exchanger transporter 1 (URAT1) inhibitor developed by Ardea Biosciences (a subsidiary of AstraZeneca) for the treatment of hyperuricemia assocd. with gout. It reduces serum uric acid (sUA) levels by inhibiting the function of the transporter proteins (URAT1 and org. anion transporter 4) involved in uric acid reabsorption in the kidney. In Dec. 2015, lesinurad was approved in the USA as combination therapy with a xanthine oxidase inhibitor for the treatment of hyperuricemia assocd. with gout in patients who have not achieved sUA target levels with a xanthine oxidase inhibitor alone. Lesinurad has also received a pos. opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use for this indication and is in phase III development as a combination therapy in several other countries. This article summarizes the milestones in the development of lesinurad leading to this first approval for hyperuricemia assocd. with gout.
- 47Pace, J. R.; DeBerardinis, A. M.; Sail, V.; Tacheva-Grigorova, S. K.; Chan, K. A.; Tran, R.; Raccuia, D. S.; Wechsler-Reya, R. J.; Hadden, M. K. Repurposing the clinically efficacious antifungal agent itraconazole as an anticancer chemotherapeutic. J. Med. Chem. 2016, 59, 3635– 3649, DOI: 10.1021/acs.jmedchem.5b01718[ACS Full Text], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XkvVOrt74%253D&md5=c7132006ac3bc3a6d74828d1aa3b0702Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer ChemotherapeuticPace, Jennifer R.; DeBerardinis, Albert M.; Sail, Vibhavari; Tacheva-Grigorova, Silvia K.; Chan, Kelly A.; Tran, Raymond; Raccuia, Daniel S.; Wechsler-Reya, Robert J.; Hadden, M. KyleJournal of Medicinal Chemistry (2016), 59 (8), 3635-3649CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole (ITZ) is an FDA-approved member of the triazole class of antifungal agents. Two recent drug repurposing screens identified ITZ as a promising anticancer chemotherapeutic that inhibits both the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized and evaluated first- and second-generation ITZ analogs for their anti-Hh and antiangiogenic activities to probe more fully the structural requirements for these anticancer properties. Our overall results suggest that the triazole functionality is required for ITZ-mediated inhibition of angiogenesis but that it is not essential for inhibition of Hh signaling. The synthesis and evaluation of stereochem. defined des-triazole ITZ analogs also provides key information as to the optimal configuration around the dioxolane ring of the ITZ scaffold. Finally, the results from our studies suggest that two distinct cellular mechanisms of action govern the anticancer properties of the ITZ scaffold.
- 48(a) Shi, W.; Nacev, B. A.; Aftab, B. T.; Head, S.; Rudin, C. M.; Liu, J. O. Itraconazole side chain analogues: structure-activity relationship studies for inhibition of endothelial cell proliferation, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and hedgehog signaling. J. Med. Chem. 2011, 54, 7363– 7674, DOI: 10.1021/jm200944b[ACS Full Text.], [CAS], Google Scholar48ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1Onsb7M&md5=69caea82df24ba45e31c48dd326f8c5bItraconazole Side Chain Analogues: Structure-Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog SignalingShi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O.Journal of Medicinal Chemistry (2011), 54 (20), 7363-7374CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogs of itraconazole with greater potency and to understand the structure-activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogs were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this anal., we have identified analogs with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR anal. of these activities revealed that potent activity of the analogs against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in compn. with branching at the α or β position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-Bu side chain can lead to enhancement of the biol. activity of itraconazole.(b) Li, Y.; Pasunooti, K. K.; Li, R. J.; Liu, W.; Head, S. A.; Shi, W. Q.; Liu, J. O. Novel tetrazole-containing analogs of itraconazole as potent anti-angiogenic agents with reduced CYP3A4 inhibition. J. Med. Chem. 2018, 61, 11158, DOI: 10.1021/acs.jmedchem.8b01252[ACS Full Text], [CAS], Google Scholar48bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlCmsb7J&md5=6337b8db0718df19a55a54329badca15Novel Tetrazole-Containing Analogues of Itraconazole as Potent Antiangiogenic Agents with Reduced Cytochrome P450 3A4 InhibitionLi, Yingjun; Pasunooti, Kalyan Kumar; Li, Ruo-Jing; Liu, Wukun; Head, Sarah A.; Shi, Wei Q.; Liu, Jun O.Journal of Medicinal Chemistry (2018), 61 (24), 11158-11168CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Itraconazole has been found to possess potent antiangiogenic activity, exhibiting promising antitumor activity in several human clin. studies. The wider use of itraconazole in the treatment of cancer, however, has been limited by its potent inhibition of the drug metabolizing enzyme cytochrome P 450 3A4 (CYP3A4). In an effort to eliminate the CYP3A4 inhibition while retaining its antiangiogenic activity, we designed and synthesized a series of derivs. in which the 1,2,4-triazole ring is replaced with various azoles and nonazoles. Among these analogs, I with tetrazole in place of 1,2,4-triazole exhibited optimal inhibition of human umbilical vein endothelial cell proliferation with an IC50 of 73 nM without a significant effect on CYP3A4 (EC50 > 20 μM). Similar to itraconazole, I induced Niemann-Pick C phenotype (NPC phenotype) and blocked AMPK/mechanistic target of rapamycin signaling. These results suggest that I is a promising angiogenesis inhibitor that can be used in combination with most other known anticancer drugs.
- 49Thompson, A. M.; O’Connor, P. D.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Martin, D.; Franzblau, S. G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W. A. Repositioning antitubercular 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for neglected tropical diseases: structure-activity studies on a preclinical candidate for visceral leishmaniasis. J. Med. Chem. 2016, 59, 2530– 2550, DOI: 10.1021/acs.jmedchem.5b01699[ACS Full Text], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmtbY%253D&md5=9eebc55cc434cc4dec0692bef5bbed98Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure-Activity Studies on a Preclinical Candidate for Visceral LeishmaniasisThompson, Andrew M.; O'Connor, Patrick D.; Blaser, Adrian; Yardley, Vanessa; Maes, Louis; Gupta, Suman; Launay, Delphine; Martin, Denis; Franzblau, Scott G.; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A.Journal of Medicinal Chemistry (2016), 59 (6), 2530-2550CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole derivs. were initially studied for tuberculosis within a backup program for the clin. trial agent pretomanid (PA-824). Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Addnl. work was then conducted to delineate its essential structural features, aiming to improve soly. and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well-tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of Ph rings by pyridine. Several less lipophilic analogs displayed improved aq. soly., particularly at low pH, although stability toward liver microsomes was highly variable. Upon evaluation in a mouse model of acute Leishmania donovani infection,phenylpyridine deriv. I stood out, providing efficacy surpassing that of the original preclin. lead.
- 50Turk, S.; Merget, B.; Eid, S.; Fulle, S. From cancer to pain target by automated selectivity inversion of a clinical candidate. J. Med. Chem. 2018, 61, 4851– 4859, DOI: 10.1021/acs.jmedchem.8b00140[ACS Full Text], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hurc%253D&md5=8e29a51d656eb52a41d9abc6fc22ca59From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical CandidateTurk, Samo; Merget, Benjamin; Eid, Sameh; Fulle, SimoneJournal of Medicinal Chemistry (2018), 61 (11), 4851-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Elimination of inadvertent binding is crucial for inhibitor design targeting conserved protein classes like kinases. Compds. in clin. trials provide a rich source for initiating drug design efforts by exploiting such secondary binding events. Considering both aspects, we shifted the selectivity of tozasertib, originally developed against AurA as cancer target, toward the pain target TrkA. First, selectivity-detg. features in binding pockets were identified by fusing interaction grids of several key and off-target conformations. A focused library was subsequently created and prioritized using a multiobjective selection scheme that filters for selective and highly active compds. based on orthogonal methods grounded in computational chem. and machine learning. Eighteen high-ranking compds. were synthesized and exptl. tested. The top-ranked compd. has 10000-fold improved selectivity vs. AurA, nanomolar cellular activity, and is highly selective in a kinase panel. This was achieved in a single round of automated in silico optimization, highlighting the power of recent advances in computer-aided drug design to automate design and selection processes.
- 51Perlmutter, J. I.; Forbes, L. T.; Krysan, D. J.; Ebsworth-Mojica, K.; Colquhoun, J. M.; Wang, J. L.; Dunman, P. M.; Flaherty, D. P. Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus. J. Med. Chem. 2014, 57, 8540– 8562, DOI: 10.1021/jm5010682[ACS Full Text], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFyjtb%252FI&md5=190dd3fd565b52b2d693a475c4cb62c1Repurposing the Antihistamine Terfenadine for Antimicrobial Activity against Staphylococcus aureusPerlmutter, Jessamyn I.; Forbes, Lauren T.; Krysan, Damian J.; Ebsworth-Mojica, Katherine; Colquhoun, Jennifer M.; Wang, Jenna L.; Dunman, Paul M.; Flaherty, Daniel P.Journal of Medicinal Chemistry (2014), 57 (20), 8540-8562CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-pos. bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogs with several modifications providing increased activity vs. S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compds. to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogs provide a novel structural class of antimicrobial compds. with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.
- 52Dilly, S.; Fotso Fotso, A.; Lejal, N.; Zedda, G.; Chebbo, M.; Rahman, F.; Companys, S.; Bertrand, H. C.; Vidic, J.; Noiray, M.; Alessi, M. C.; Tarus, B.; Quideau, S.; Riteau, B.; Slama-Schwok, A. From naproxen repurposing to naproxen analogues and their antiviral activity against influenza A virus. J. Med. Chem. 2018, 61, 7202– 7217, DOI: 10.1021/acs.jmedchem.8b00557[ACS Full Text], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGit7jI&md5=a3d21246bea09e82edd808d1e14a54eeFrom Naproxen Repurposing to Naproxen Analogues and Their Antiviral Activity against Influenza A VirusDilly, Sebastien; Fotso Fotso, Aurelien; Lejal, Nathalie; Zedda, Gloria; Chebbo, Mohamad; Rahman, Fryad; Companys, Simon; Bertrand, Helene C.; Vidic, Jasmina; Noiray, Magali; Alessi, Marie-Christine; Tarus, Bogdan; Quideau, Stephane; Riteau, Beatrice; Slama-Schwok, AnnyJournal of Medicinal Chemistry (2018), 61 (16), 7202-7217CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The nucleoprotein (NP) of influenza A virus (IAV) required for IAV replication is a promising target for new antivirals. The authors previously identified by in silico screening naproxen being a dual inhibitor of NP and cyclooxygenase COX2, thus combining antiviral and anti-inflammatory effects. However, the recently shown strong COX2 antiviral potential makes COX2 inhibition undesirable. Here the authors designed and synthesized two new series of naproxen analogs called derivs. 2, 3 (5-(4-aminophenoxy)-2-(6-methoxynaphthalen-2-yl)isophthalic acid), and 4 (4-(4-aminophenoxy)-2-(6-methoxynaphthalen-2-yl)isophthalic acid) targeting highly conserved residues of the RNA binding groove, stabilizing NP monomer without inhibiting COX2. Deriv. 2 presented improved antiviral effects in infected cells compared to that of naproxen and afforded a total protection of mice against a lethal viral challenge. Deriv. 4 also protected infected cells challenged with circulating 2009-pandemic and oseltamivir-resistant H1N1 virus. This improved antiviral effect likely results from derivs. 2 and 4 inhibiting NP-RNA and NP-polymerase acidic subunit PA N-terminal interactions.
- 53Mohiuddin, G.; Khan, K. M.; Salar, U.; Kanwal; Wadood, A.; Riaz, M.; Perveen, S. Biology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivatives. Bioorg. Chem. 2019, 83, 29– 46, DOI: 10.1016/j.bioorg.2018.10.021[Crossref], [PubMed], [CAS], Google Scholar53https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFeisrzN&md5=7577a5d8e6672125f32e3d4bd16fc6bfBiology-oriented drug synthesis (BIODS), in vitro urease inhibitory activity, and in silico study of S-naproxen derivativesMohiuddin, Ghulam; Khan, Khalid Mohammed; Salar, Uzma; Kanwal; Lodhi, Muhammad Arif; Wadood, Abdul; Riaz, Muhammad; Perveen, ShahnazBioorganic Chemistry (2019), 83 (), 29-46CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)Current study is based on the biol.-oriented drug synthesis (BIODS) of S-naproxen (NSAID) derivs. and the evaluation of their urease inhibitory potential. In this regard, a variety of S-naproxen derivs. 2-39 including hydrazide 1, Schiff bases 2-21, aroyl substituted hydrazides 22-24, sulfohydrazides 25-34, 2-mercapto oxadiazole 35, phenacyl substituted 2-mercapto oxadiazoles 36-39 were synthesized under the umbrella of BIODS by simple chem. transformation of its pharmacophoric carboxylic group. Compds. 1-39 were evaluated for in vitro urease inhibitory activity and most of them showed good to moderate inhibitory potential in the range of IC50 = 14.01±0.23-76.43±0.8 μM as compared to std. acetohydroxamic acid (IC50 = 27.0±0.5 μM). Limited structure-activity relationship (SAR) was established in order to rationalize the participation of varying groups (R) in the inhibitory potential of compds. Mol. docking study on all active compds. was also carried out to decipher the interactions detail of the ligand with the receptors of active site of enzyme.
- 54Mercorelli, B.; Palu, G.; Loregian, A. Drug repurposing for viral infectious diseases: how far are we?. Trends Microbiol. 2018, 26, 865– 876, DOI: 10.1016/j.tim.2018.04.004[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXos1Oitrc%253D&md5=6caf97ff2453b3dadcc0b54124a25d69Drug Repurposing for Viral Infectious Diseases: How Far Are WeMercorelli, Beatrice; Palu, Giorgio; Loregian, AriannaTrends in Microbiology (2018), 26 (10), 865-876CODEN: TRMIEA; ISSN:0966-842X. (Elsevier Ltd.)A review. Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral mols. and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery.
- 55Debing, Y.; Neyts, J.; Delang, L. The future of antivirals: broad-spectrum inhibitors. Curr. Opin. Infect. Dis. 2015, 28, 596– 602, DOI: 10.1097/QCO.0000000000000212[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVartLfF&md5=51aadcc17323e142ef8ba04f7b60b6c1The future of antivirals: broad-spectrum inhibitorsDebing, Yannick; Neyts, Johan; Delang, LeenCurrent Opinion in Infectious Diseases (2015), 28 (6), 596-602CODEN: COIDE5; ISSN:0951-7375. (Lippincott Williams & Wilkins)Purpose of review: Potent antivirals are successfully used for the treatment of infections with herpesviruses, hepatitis B and C viruses, HIV, and with some success for influenza viruses. However, no selective inhibitors are available for a multitude of medically important viruses, most of which are (re-)emerging RNA viruses. As it is impossible to develop drugs against each of these viruses, broad-spectrum antiviral agents (BSAA) are a prime strategy to cope with this challenge. Recent findings: We propose four categories of antiviral mols. that hold promise as BSAA. Several nucleoside analogs with broad antiviral activity have been described and given the relatively conserved nature of viral polymerases, it may be possible to develop more broad-spectrum nucleoside analogs. A no. of viral proteins are relatively conserved between families and may also be interesting targets. Host-targeting antiviral drugs such as modulators of lipid metab. and cyclophilin inhibitors can be explored as well. Finally, the potent and broad antiviral function of the immune system can be exploited by the development of immune-modulating BSAA. Summary: Despite the recent advances, the BSAA field is still in its infancy. Nevertheless, the discovery and development of such mols. will be a key aim of antiviral research in the coming decades.
- 56Sacramento, C. Q.; de Melo, G. R.; de Freitas, C. S.; Rocha, N.; Hoelz, L. V.; Miranda, M.; Fintelman-Rodrigues, N.; Marttorelli, A.; Ferreira, A. C.; Barbosa-Lima, G.; Abrantes, J. L.; Vieira, Y. R.; Bastos, M. M.; de Mello Volotao, E.; Nunes, E. P.; Tschoeke, D. A.; Leomil, L.; Loiola, E. C.; Trindade, P.; Rehen, S. K.; Bozza, F. A.; Bozza, P. T.; Boechat, N.; Thompson, F. L.; de Filippis, A. M.; Bruning, K.; Souza, T. M. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci. Rep. 2017, 7, 40920, DOI: 10.1038/srep40920[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVantL4%253D&md5=944e73ce2f50fa92d5d18e230a58ff2cThe clinically approved antiviral drug sofosbuvir inhibits Zika virus replicationSacramento, Carolina Q.; de Melo, Gabrielle R.; de Freitas, Caroline S.; Rocha, Natasha; Hoelz, Lucas Villas Boas; Miranda, Milene; Fintelman-Rodrigues, Natalia; Marttorelli, Andressa; Ferreira, Andre C.; Barbosa-Lima, Giselle; Abrantes, Juliana L.; Vieira, Yasmine Rangel; Bastos, Monica M.; de Mello Volotao, Eduardo; Nunes, Estevao Portela; Tschoeke, Diogo A.; Leomil, Luciana; Loiola, Erick Correia; Trindade, Pablo; Rehen, Stevens K.; Bozza, Fernando A.; Bozza, Patricia T.; Boechat, Nubia; Thompson, Fabiano L.; de Filippis, Ana M. B.; Bruning, Karin; Souza, Thiago Moreno L.Scientific Reports (2017), 7 (), 40920CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clin. significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurol. disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clin. approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addn. to the direct inhibition of the viral RNA polymerase, we obsd. that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.
- 57Abdelnabi, R.; Morais, A. T. S.; Leyssen, P.; Imbert, I.; Beaucourt, S.; Blanc, H.; Froeyen, M.; Vignuzzi, M.; Canard, B.; Neyts, J.; Delang, L. Understanding the mechanism of the broad-spectrum antiviral activity of favipiravir (T-705): key role of the F1 motif of the viral polymerase. J. Virol. 2017, 91, e00487, DOI: 10.1128/JVI.00487-17[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1elsrzE&md5=0bcc12b05ab01929161119020c735cf7Understanding the mechanism of the broad-spectrum antiviral activity of favipiravir (T-705): key role of the F1 motif of the viral polymeraseAbdelnabi, Rana; Silveira de Morais, Ana Theresa; Leyssen, Pieter; Imbert, Isabelle; Beaucourt, Stephanie; Blanc, Herve; Froeyen, Mathy; Vignuzzi, Marco; Canard, Bruno; Neyts, Johan; Delang, LeenJournal of Virology (2017), 91 (12), e00487-17/1-e00487-17/15CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)Favipiravir (T-705) is a broad-spectrum antiviral agent that has been approved in Japan for the treatment of influenza virus infections. T-705 also inhibits the replication of various RNA viruses, including chikungunya virus (CHIKV). We demonstrated earlier that the K291R mutation in the F1 motif of the RNA-dependent RNA polymerase (RdRp) of CHIKV is responsible for low-level resistance to T-705. Interestingly, this lysine is highly conserved in the RdRp of pos.-sense singlestranded RNA (+ssRNA) viruses. To obtain insights into the unique broad-spectrum antiviral activity of T-705, we explored the role of this lysine using another +ssRNA virus, namely, coxsackievirus B3 (CVB3). Introduction of the corresponding K-to-R substitution in the CVB3 RdRp (K159R) resulted in a nonviable virus. Replication competence of the K159R variant was restored by spontaneous acquisition of an A239G substitution in the RdRp. A mutagenesis anal. at position K159 identified the K159M variant as the only other viable variant which had also acquired the A239G substitution. The K159 substitutions markedly decreased the processivity of the purified viral RdRp, which was restored by the introduction of the A239G mutation. The K159R A239G and K159M A239G variants proved, surprisingly, more susceptible than the wild-type virus to T-705 and exhibited lower fidelity in polymerase assays. Furthermore, the K159R A239G variant was found to be highly attenuated in mice. We thus demonstrate that the conserved lysine in the F1 motif of the RdRp of +ssRNA viruses is involved in the broad-spectrum antiviral activity of T-705 and that it is a key amino acid for the proper functioning of the enzyme.
- 58Rossignol, J. F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 2014, 110, 94– 103, DOI: 10.1016/j.antiviral.2014.07.014[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtleisL%252FK&md5=12dd8a143876626fc31303da2c5f24c4Nitazoxanide: A first-in-class broad-spectrum antiviral agentRossignol, Jean-FrancoisAntiviral Research (2014), 110 (), 94-103CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)A review. Originally developed and commercialized as an antiprotozoal agent, nitazoxanide was later identified as a first-in-class broad-spectrum antiviral drug and has been repurposed for the treatment of influenza. A Phase 2b/3 clin. trial recently published in The Lancet Infectious Diseases found that oral administration of nitazoxanide 600 mg twice daily for five days reduced the duration of clin. symptoms and reduced viral shedding compared to placebo in persons with lab.-confirmed influenza. The same study also suggested a potential benefit for subjects with influenza-like illness who did not have influenza or other documented respiratory viral infection. From a chem. perspective, nitazoxanide is the scaffold for a new class of drugs called thiazolides. These small-mol. drugs target host-regulated processes involved in viral replication. Nitazoxanide is orally bioavailable and safe with extensive post-marketing experience involving more than 75 million adults and children. A new dosage formulation of nitazoxanide is presently undergoing global Phase 3 clin. development for the treatment of influenza. Nitazoxanide inhibits a broad range of influenza A and B viruses including influenza A(pH1N1) and the avian A(H7N9) as well as viruses that are resistant to neuraminidase inhibitors. It is synergistic with neuraminidase inhibitors, and combination therapy with oseltamivir is being studied in humans as part of ongoing Phase 3 clin. development. Nitazoxanide also inhibits the replication of a broad range of other RNA and DNA viruses including respiratory syncytial virus, parainfluenza, coronavirus, rotavirus, norovirus, hepatitis B, hepatitis C, dengue, yellow fever, Japanese encephalitis virus and human immunodeficiency virus in cell culture assays. Clin. trials have indicated a potential role for thiazolides in treating rotavirus and norovirus gastroenteritis and chronic hepatitis B and chronic hepatitis C. Ongoing and future clin. development is focused on viral respiratory infections, viral gastroenteritis and emerging infections such as dengue fever.
- 59(a) Li, C. C.; Wang, X. J.; Wang, H. R. Repurposing host-based therapeutics to control coronavirus and influenza virus. Drug Discov. Today 2019, 24, 726, DOI: 10.1016/j.drudis.2019.01.018[Crossref], [PubMed], [CAS], Google Scholar.59ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjot1KrsQ%253D%253D&md5=63715dbcbaa48ee2a7cd6e1adde992b9Repurposing host-based therapeutics to control coronavirus and influenza virusLi Cui-Cui; Wang Xiao-Jia; Wang Hwa-Chain RobertDrug discovery today (2019), 24 (3), 726-736 ISSN:.The development of highly effective antiviral agents has been a major objective in virology and pharmaceutics. Drug repositioning has emerged as a cost-effective and time-efficient alternative approach to traditional drug discovery and development. This new shift focuses on the repurposing of clinically approved drugs and promising preclinical drug candidates for the therapeutic development of host-based antiviral agents to control diseases caused by coronavirus and influenza virus. Host-based antiviral agents target host cellular machineries essential for viral infections or innate immune responses to interfere with viral pathogenesis. This review discusses current knowledge, prospective applications and challenges in the repurposing of clinically approved and preclinically studied drugs for newly indicated antiviral therapeutics.(b) Meng, W.; Wang, X. J.; Wang, H. R. Targeting nuclear proteins for control of viral replication. Crit. Rev. Microbiol. 2019, 1– 19, DOI: 10.1080/1040841X.2018.1553848[Crossref], [PubMed], [CAS], Google Scholar59bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cjjsVygug%253D%253D&md5=2220b446fbf713bc18f5ecae662a22f0Targeting nuclear proteins for control of viral replicationMeng Wen; Wang Xiao-Jia; Wang Hwa-Chain RobertCritical reviews in microbiology (2019), (), 1-19 ISSN:.Viruses are obligate intracellular parasites that exploit host cell machineries for replication. In this review, we focus on the current understanding of host cell nuclear proteins whose translocation from the nucleus to cytoplasm is induced and utilized by viruses to support viral replication and infection. Utilization of nuclear proteins for viral replication and infection involves disruption of nuclear import, enhancement of nuclear export, removal of nuclear localization signal (NLS) from nuclear proteins and alteration of nuclear pore complexes (NPCs) to cooperatively support viral replication. Understanding of nucleo-cytoplasmic transport system, and associated mechanisms, utilized by viruses will advance therapeutic development of strategies to produce optimal antiviral agents effective in control of viral diseases.
- 60Tong, X.; Smith, J.; Bukreyeva, N.; Koma, T.; Manning, J. T.; Kalkeri, R.; Kwong, A. D.; Paessler, S. Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. Antiviral Res. 2018, 149, 34– 40, DOI: 10.1016/j.antiviral.2017.11.004[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVSiu7bK&md5=959c9e0115298b3f1299d79a00a0c89aMerimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogensTong, Xiao; Smith, Jeanon; Bukreyeva, Natalya; Koma, Takaaki; Manning, John T.; Kalkeri, Raj; Kwong, Ann D.; Paessler, SlobodanAntiviral Research (2018), 149 (), 34-40CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to abnormal pregnancies, fetal death, microcephaly, and Guillain-Barre´ syndrome in humans. Merimepodib (MMPD, VX-497), a potent inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), has shown antiviral activity against HCV and a variety of DNA and RNA viruses in vitro. In this report, we expand the antiviral spectrum of MMPD, and demonstrate that MMPD inhibits ZIKV RNA replication with an EC50 of 0.6 μM. Furthermore, MMPD reduces the virus prodn. of ZIKV as well as several other important emerging viral pathogens such as Ebola, Lassa, Chikungunya, and Junin viruses. The inhibition can be reversed by addn. of exogenous guanosine to culture media, consistent with the mechanism of action of MMPD as an IMPDH inhibitor. We also provide evidence that MMPD can be used in combination with other antivirals such as ribavirin and T-705 (favipiravir) to enhance suppression of virus prodn.
- 61Dang, W.; Yin, Y.; Wang, Y.; Wang, W.; Su, J.; Sprengers, D.; van der Laan, L. J. W.; Felczak, K.; Pankiewicz, K. W.; Chang, K. O.; Koopmans, M. P. G.; Metselaar, H. J.; Peppelenbosch, M. P.; Pan, Q. Inhibition of calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replication. Antimicrob. Agents Chemother. 2017, 61, e01095– 17, DOI: 10.1128/AAC.01095-17[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpsl2jtLc%253D&md5=248ed1305a71c7e46e6933a4fc5f46e7Inhibition of calcineurin or IMP dehydrogenase exerts moderate to potent antiviral activity against norovirus replicationDang, Wen; Yin, Yuebang; Wang, Yijin; Wang, Wenshi; Su, Junhong; Sprengers, Dave; van der Laan, Luc J. W.; Felczak, Krzysztof; Pankiewicz, Krzysztof W.; Chang, Kyeong-Ok; Koopmans, Marion P. G.; Metselaar, Herold J.; Peppelenbosch, Maikel P.; Pan, QiuweiAntimicrobial Agents and Chemotherapy (2017), 61 (11), e01095-17/1-e01095-17/17CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concn., therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis.
- 62Hu, J.; Ma, L.; Wang, H.; Yan, H.; Zhang, D.; Li, Z.; Jiang, J.; Li, Y. A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5′-Monophospate dehydrogenase activity. Virol J. 2017, 14, 55, DOI: 10.1186/s12985-017-0724-6[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvVags7o%253D&md5=5478507bdcb798e9dd77da1bc0a84a26A novel benzo-heterocyclic amine derivative N30 inhibits influenza virus replication by depression of Inosine-5'-Monophospate Dehydrogenase activityHu, Jin; Ma, Linlin; Wang, Huiqiang; Yan, Haiyan; Zhang, Dajun; Li, Zhuorong; Jiang, Jiandong; Li, YuhuanVirology Journal (2017), 14 (), 55/1-55/9CODEN: VJIOA4; ISSN:1743-422X. (BioMed Central Ltd.)Influenza virus is still a huge threat to the world-wide public health. Host inosine-5'- monophosphate dehydrogenase (IMPDH) involved in the synthesis of guanine nucleotides, is known to be a potential target to inhibit the replication of viruses. Herein, we evaluated antiviral activity of a benzo-heterocyclic amine deriv. N30, which was designed to inhibit IMPDH. The results demonstrated that N30 inhibited the replication of H1N1, H3N2, influenza B viruses, including oseltamivir and amantadine resistant strains in vitro. Mechanistically, neuraminidase inhibition assay and hemagglutination inhibition assay suggested that N30 did not directly target the two envelope glycoproteins required for viral adsorption or release. Instead, the compd. could depress the activity of IMPDH type II. Based on these findings, we further confirmed that N30 provided a strong inhibition on the replication of respiratory syncytial virus, coronavirus, enterovirus 71 and a diverse strains of coxsackie B virus. We identified the small mol. N30, as an inhibitor of IMPDH, might be a potential candidate to inhibit the replication of various viruses.
- 63Nair, V.; Chi, G.; Shu, Q.; Julander, J.; Smee, D. F. A heterocyclic molecule with significant activity against dengue virus. Bioorg. Med. Chem. Lett. 2009, 19, 1425– 1427, DOI: 10.1016/j.bmcl.2009.01.031[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXit1Wmsb8%253D&md5=87f61298ea3e49d74a87389aca4a36acA heterocyclic molecule with significant activity against dengue virusNair, Vasu; Chi, Guochen; Shu, Qingning; Julander, Justin; Smee, Donald F.Bioorganic & Medicinal Chemistry Letters (2009), 19 (5), 1425-1427CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)The prepn. of two uracil-based multifunctional compds I [X = N (II), CH] was reported. One of these compds., II, showed strong activity against dengue virus. It also exhibited low activity against a few other RNA viruses, but was highly active against yellow fever virus, a related flavivirus. It is likely that the mechanism of action of the antiviral activity of this compd. is through its inhibition of the enzyme, inosine monophosphate dehydrogenase (IMPDH). Mol. modeling studies revealed that the compd. can have specific hydrogen bonding interactions with a no. of amino acids in the active site of IMPDH, a stacking interaction with the bound natural substrate, IMP, and the ability to interfere with the binding of NAD+ with IMPDH, prior to the hydration step.
- 64Mejdrova, I.; Chalupska, D.; Plackova, P.; Muller, C.; Sala, M.; Klima, M.; Baumlova, A.; Hrebabecky, H.; Prochazkova, E.; Dejmek, M.; Strunin, D.; Weber, J.; Lee, G.; Matousova, M.; Mertlikova-Kaiserova, H.; Ziebuhr, J.; Birkus, G.; Boura, E.; Nencka, R. Rational design of novel highly potent and selective phosphatidylinositol 4-kinase IIIbeta (PI4KB) inhibitors as broad-spectrum antiviral agents and tools for chemical biology. J. Med. Chem. 2017, 60, 100– 118, DOI: 10.1021/acs.jmedchem.6b01465[ACS Full Text], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGitbbM&md5=d0cc3a744b59313677b10454012c495bRational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical BiologyMejdrova, Ivana; Chalupska, Dominika; Plackova, Pavla; Muller, Christin; Sala, Michal; Klima, Martin; Baumlova, Adriana; Hrebabecky, Hubert; Prochazkova, Eliska; Dejmek, Milan; Strunin, Dmytro; Weber, Jan; Lee, Gary; Matousova, Marika; Mertlikova-Kaiserova, Helena; Ziebuhr, John; Birkus, Gabriel; Boura, Evzen; Nencka, RadimJournal of Medicinal Chemistry (2017), 60 (1), 100-118CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various pos.-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, the authors report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These "hybrids" not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compds. exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. The authors' crystallog. anal. unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.
- 65Bauer, L.; Ferla, S.; Head, S. A.; Bhat, S.; Pasunooti, K. K.; Shi, W. Q.; Albulescu, L.; Liu, J. O.; Brancale, A.; van Kuppeveld, F. J. M.; Strating, J. R. P. M. Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP). Antiviral Res. 2018, 156, 55– 63, DOI: 10.1016/j.antiviral.2018.05.010[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWitbjO&md5=457ee3152a08fd4640aa6e87be8467c5Structure-activity relationship study of itraconazole, a broad-range inhibitor of picornavirus replication that targets oxysterol-binding protein (OSBP)Bauer, Lisa; Ferla, Salvatore; Head, Sarah A.; Bhat, Shridhar; Pasunooti, Kalyan K.; Shi, Wei Q.; Albulescu, Lucian; Liu, Jun O.; Brancale, Andrea; van Kuppeveld, Frank J. M.; Strating, Jeroen R. P. M.Antiviral Research (2018), 156 (), 55-63CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Itraconazole (ITZ) is a well-known, FDA-approved antifungal drug that is also in clin. trials for its anticancer activity. ITZ exerts its anticancer activity through several disparate targets and pathways. ITZ inhibits angiogenesis by hampering the functioning of the vascular endothelial growth receptor 2 (VEGFR2) and by indirectly inhibiting mTOR signaling. Furthermore, ITZ directly inhibits the growth of several types of tumor cells by antagonizing Hedgehog signaling. Recently, we reported that ITZ also has broad-spectrum antiviral activity against enteroviruses, cardioviruses and hepatitis C virus, independent of established ITZ-activities but instead via a novel target, oxysterol-binding protein (OSBP), a cellular lipid shuttling protein. In this study, we analyzed which structural features of ITZ are important for the OSBP-mediated antiviral activity. The backbone structure, consisting of five rings, and the sec-Bu chain are important for antiviral activity, whereas the triazole moiety, which is crit. for antifungal activity, is not. The features required for OSBP-mediated antiviral activity of ITZ overlap mostly with published features required for inhibition of VEGFR2 trafficking, but not Hh signaling. Furthermore, we use in silico studies to explore how ITZ could bind to OSBP. Our data show that several pharmacol. activities of ITZ can be uncoupled, which is a crit. step in the development of ITZ-based antiviral compds. with greater specificity and reduced off-target effects.
- 66(a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. Rings in drugs. J. Med. Chem. 2014, 57, 5845– 5859, DOI: 10.1021/jm4017625[ACS Full Text.], [CAS], Google Scholar66ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlCntbc%253D&md5=c84ce84b8698eb6fad38fa82b0ab4912Rings in DrugsTaylor, Richard D.; MacCoss, Malcolm; Lawson, Alastair D. G.Journal of Medicinal Chemistry (2014), 57 (14), 5845-5859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, time-lines, mol. property space, and the application of these rings in different therapeutic areas and target classes. This anal. shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on av. six new ring systems enter drug space each year and approx. 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chem. novelty of drugs and potentially efficient ways to assess compd. libraries and develop compds. from hit identification to lead optimization and beyond.(b) Taylor, R. D.; MacCoss, M.; Lawson, A. D. Combining molecular scaffolds from FDA approved drugs: application to drug discovery. J. Med. Chem. 2017, 60, 1638– 1647, DOI: 10.1021/acs.jmedchem.6b01367[ACS Full Text], [CAS], Google Scholar66bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVGrurrJ&md5=b4fea6326e337e85d39aa827a180b634Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug DiscoveryTaylor, Richard D.; MacCoss, Malcolm; Lawson, Alastair D. G.Journal of Medicinal Chemistry (2017), 60 (5), 1638-1647CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The authors have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in-silico database of approx. 14 million mols. This virtual library was compared with mol. databases of published and com. available compds. to assess the prevalence of drug ring combinations in modern medicinal chem. and to identify areas of under-represented, but clin. validated, chem. space. From the 10 trillion mol. comparisons, the authors found that less than 1% of the possible combinations of drug ring systems appear in com. available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small mol. drug discovery, as based on the previous anal. (Taylor et al. J. Med. Chem. 2014; 57: 5845-9) approx. 70% of all new drugs are made up of only ring systems that have been used in existing drugs.
- 67(a) Song, Y.; Chen, W.; Kang, D.; Zhang, Q.; Zhan, P.; Liu, X. ″Old friends in new guise″: exploiting privileged structures for scaffold re-evolution/refining. Comb. Chem. High Throughput Screening 2014, 17, 536– 553, DOI: 10.2174/1386207317666140122101631[Crossref], [PubMed], [CAS], Google Scholar.67ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFOgsLvF&md5=4353d66dbd43353caefcd150938f94cd"Old Friends in New Guise": Exploiting Privileged Structures for Scaffold Re-Evolution/RefiningSong, Yu'ning; Chen, Wenmin; Kang, Dongwei; Zhang, Qingzhu; Zhan, Peng; Liu, XinyongCombinatorial Chemistry & High Throughput Screening (2014), 17 (6), 536-553CODEN: CCHSFU; ISSN:1386-2073. (Bentham Science Publishers Ltd.)A review. The attempts to increase novel drug productivity through creative discovery technologies have fallen short of producing the satisfactory results. For these reasons, evolved from the concept of drug repositioning, "privileged structure"-guided scaffold re-evolution/refining is a primary strategy to identify structurally novel chemotypes by modifying the central core structure and the side-chain of the existing active compds., or to exploit undescribed bioactivites by making full use of readily derivatized motifs with well-established synthetic protocols. Herein, we review the basic tricks of exploiting privileged structures for scaffold re-evolution/refining. The power of this strategy is exemplified in the discovery of other new therapeutic applications by refining privileged structures in anti-viral agents.(b) Li, Z.; Zhan, P.; Liu, X. 1,3,4-oxadiazole: a privileged structure in antiviral agents. Mini-Rev. Med. Chem. 2011, 11, 1130– 1142, DOI: 10.2174/138955711797655407[Crossref], [PubMed], [CAS], Google Scholar.67bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFakt7jJ&md5=440a9792afb05d86aafaf53379861dcb1,3,4-oxadiazole: a privileged structure in antiviral agentsLi, Z.; Zhan, P.; Liu, X.Mini-Reviews in Medicinal Chemistry (2011), 11 (13), 1130-1142CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)A review. 1,3,4-Oxadiazole, a privileged structure, endows its derivs. with broad and potent biol. functions, esp. in antiviral activities, including anti-HIV, anti-HCV, anti-HBV, anti-HSV activities, etc. Mol. modeling and pharmacokinetic studies have demonstrated that the introduction of 1,3,4-oxadiazole ring to the inhibitors can change their polarity, flexibility as well as metabolic stability, and 1,3,4-oxadiazole scaffold can also act as acceptors of hydrogen bonds formation, which make it possible to be used as a isosteric substituent for amide or ester groups. This review focuses on the recent advances in the synthesis of 1,3,4-oxadiazole ring and mainly the discovery, biol. activities investigations and structural modifications of several distinct classes of 1,3,4-oxadiazoles as potent antiviral agents. In addn., the binding models of some representative 1,3,4-oxadiazoles were also discussed, which provide rational explanation for their interesting antiviral activities, and also pave the way for further optimization of 1,3,4- oxadiazole based antiviral agents.(c) Song, Y.; Zhan, P.; Zhang, Q.; Liu, X. Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry. Curr. Pharm. Des. 2013, 19, 1528– 1548, DOI: 10.2174/138161213804805559[Crossref], [PubMed], [CAS], Google Scholar.67chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXlt1Gnsrs%253D&md5=b6ca8b08c0daadbf0b35f800266115a3Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistrySong, Yu'ning; Zhan, Peng; Zhang, Qingzhu; Liu, XinyongCurrent Pharmaceutical Design (2013), 19 (8), 1528-1548CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Pyrrolo[2,1-f][1,2,4]triazine template, a unique bridgehead nitrogen heterocycle, certainly deserves the title of "privileged scaffold" in the drug discovery field because of the versatility and potential to yield derivs. with a wide range of biol. activities, such as anti-anaplastic lymphoma kinase (ALK), Janus kinase 2 (JAK2), VEGFR-2, EGFR and/or HER2, Met kinase, p38α mitogen-activated protein (MAP) kinase and insulin-like growth factor receptor (IGF-1R) kinase activities, etc. These different biol. properties of pyrrolo[2,1-f][1,2,4]triazine derivs. have motivated new studies in searching for novel derivs. with improved activity and also other applications in pharmaceutical field. However, no systematic review is available in the literature on the pyrrolo[2,1-f][1,2,4]triazine derivs. concerning the design of potent drug-like compds. Owing to the importance of this heterocyclic system, the present paper is an attempt to the pharmacol. activities, structural modifications and the structure-activity relationship (SAR) reported for bridgehead nitrogen heterocycles in the current literature, making an effort to highlight the importance and therapeutic potentials of the pyrrolo[2,1-f][1,2,4]triazine scaffold and its bridgehead nitrogen bioisosters as heterocyclic privileged medicinal scaffolds.(d) Song, Y.; Zhan, P.; Liu, X. Heterocycle-thioacetic acid motif: a privileged molecular scaffold with potent, broad-ranging pharmacological activities. Curr. Pharm. Des. 2013, 19, 7141– 7154, DOI: 10.2174/13816128113199990505[Crossref], [PubMed], [CAS], Google Scholar.67dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhvFelur7K&md5=c2e4d68cc73d6108468a2f310f428b09Heterocycle-thioacetic Acid Motif: A Privileged Molecular Scaffold with Potent, Broad-Ranging Pharmacological ActivitiesSong, Yu'ning; Zhan, Peng; Liu, XinyongCurrent Pharmaceutical Design (2013), 19 (40), 7141-7154CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)A review. Privileged structures can bind to multiple targets with high affinity, thus aiding the discovery of novel bioactive agents. Heterocycle-thioacetic acid derivs., a group of mols. contg. a heterocycle core linked with a thioacetic acid-derived fragment, represent an important type of "privileged scaffold" possessing a wide spectrum of biol. properties. Numerous encouraging investigations demonstrated that this privileged structure should be extensively exploited for the therapeutic benefits. In view of its predominance, and on the basis of our research interest involved in this scaffold, an updated and detailed account of the pharmacol. properties of heterocycle-thioacetic acid derivs. is described in this article.(e) Zhao, F.; Liu, N.; Zhan, P.; Liu, X. Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricks. Future Med. Chem. 2015, 7, 1367– 1371, DOI: 10.4155/fmc.15.76[Crossref], [PubMed], [CAS], Google Scholar67ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1KmtrvO&md5=817927f51219a6e23073d4b26e6c1ac0Repurposing of HDAC inhibitors toward anti-hepatitis C virus drug discovery: teaching an old dog new tricksZhao, Fabao; Liu, Na; Zhan, Peng; Liu, XinyongFuture Medicinal Chemistry (2015), 7 (11), 1367-1371CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)There is no expanded citation for this reference.
- 68Zeng, L. F.; Wang, Y.; Kazemi, R.; Xu, S.; Xu, Z. L.; Sanchez, T. W.; Yang, L. M.; Debnath, B.; Odde, S.; Xie, H.; Zheng, Y. T.; Ding, J.; Neamati, N.; Long, Y. Q. Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties. J. Med. Chem. 2012, 55, 9492– 9509, DOI: 10.1021/jm300667v[ACS Full Text], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFOltrvN&md5=1dfedb7d079e37cdd5244253e351e2dfRepositioning HIV-1 Integrase Inhibitors for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold with Drug-like PropertiesZeng, Li-Fan; Wang, Yong; Kazemi, Roza; Xu, Shili; Xu, Zhong-Liang; Sanchez, Tino W.; Yang, Liu-Meng; Debnath, Bikash; Odde, Srinivas; Xie, Hua; Zheng, Yong-Tang; Ding, Jian; Neamati, Nouri; Long, Ya-QiuJournal of Medicinal Chemistry (2012), 55 (22), 9492-9509CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Among a large no. of HIV-1 integrase (IN) inhibitors, the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Labs. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clin. studies, development of L-870,810 was halted. Because of its desirable pharmacol. and pharmaceutical properties we were intrigued to design novel analogs of L-870,810 with goals to (1) improve upon limitations of naphthyridine-7-carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino-[1,6]naphthyridines, e.g. I [R = OH, NHCH2CH2OH, NHBn, etc.], were significantly cytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compds. with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases.
- 69Schwehm, C.; Kellam, B.; Garces, A. E.; Hill, S. J.; Kindon, N. D.; Bradshaw, T. D.; Li, J.; Macdonald, S. J.; Rowedder, J. E.; Stoddart, L. A.; Stocks, M. J. Design and Elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C-C chemokine receptor type 5 (CCR5), and highly potent and selective phosphoinositol-3 kinase delta (PI3Kdelta) inhibitors. J. Med. Chem. 2017, 60, 1534– 1554, DOI: 10.1021/acs.jmedchem.6b01801[ACS Full Text], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1Gjtbg%253D&md5=9128aca7e5568a89cb49addccdc3283aDesign and Elaboration of a Tractable Tricyclic Scaffold To Synthesize Druglike Inhibitors of Dipeptidyl Peptidase-4 (DPP-4), Antagonists of the C-C Chemokine Receptor Type 5 (CCR5), and Highly Potent and Selective Phosphoinositol-3 Kinase δ (PI3Kδ) InhibitorsSchwehm, Carolin; Kellam, Barrie; Garces, Aimie E.; Hill, Stephen J.; Kindon, Nicholas D.; Bradshaw, Tracey D.; Li, Jin; Macdonald, Simon J. F.; Rowedder, James E.; Stoddart, Leigh A.; Stocks, Michael J.Journal of Medicinal Chemistry (2017), 60 (4), 1534-1554CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel mol. scaffold has been synthesized, and its incorporation into new analogs of biol. active mols. across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochem. properties of the resulting inhibitors and conclude that the tractable mol. scaffold could have potential application in future drug discovery programs.
- 70John, J.; Kim, Y.; Bennett, N.; Das, K.; Liekens, S.; Naesens, L.; Arnold, E.; Maguire, A. R.; Gotte, M.; Dehaen, W.; Balzarini, J. Pronounced inhibition shift from HIV reverse transcriptase to herpetic DNA polymerases by increasing the flexibility of alpha-carboxy nucleoside phosphonates. J. Med. Chem. 2015, 58, 8110– 8127, DOI: 10.1021/acs.jmedchem.5b01180[ACS Full Text], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Kit7fO&md5=870e3e13a71997e19138133dbb3eacf2Pronounced Inhibition Shift from HIV Reverse Transcriptase to Herpetic DNA Polymerases by Increasing the Flexibility of α-Carboxy Nucleoside PhosphonatesJohn, Jubi; Kim, Youngju; Bennett, Nicholas; Das, Kalyan; Liekens, Sandra; Naesens, Lieve; Arnold, Eddy; Maguire, Anita R.; Gotte, Matthias; Dehaen, Wim; Balzarini, JanJournal of Medicinal Chemistry (2015), 58 (20), 8110-8127CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)α-Carboxynucleoside phosphonates (α-CNPs) are novel viral DNA polymerase inhibitors that do not need metabolic conversion for enzyme inhibition. The prototype contains a cyclopentyl linker between nucleobase and α-carboxyphosphonate and preferentially (50- to 100-fold) inhibits HIV-1 RT compared with herpetic DNA polymerases. A synthesis methodol. involving three steps has been developed for the synthesis of a series of novel α-CNPs, including a Rh(II)-catalyzed O-H insertion that connects the carboxyphosphonate group to a linker moiety and an attachment of a nucleobase to the other end of the linker by a Mitsunobu reaction followed by final deprotection. Replacing the cyclopentyl moiety in the prototype α-CNPs by a more flexible entity results in a selectivity shift of ∼100-fold in favor of the herpetic DNA polymerases when compared to selectivity for HIV-1 RT. The nature of the kinetic interaction of the acyclic α-CNPs against the herpetic DNA polymerases differs from the nature of the nucleobase-specific kinetic interaction of the cyclopentyl α-CNPs against HIV RT.
- 71(a) Nowotny, M. Retroviral integrase superfamily: the structural perspective. EMBO Rep. 2009, 10, 144– 151, DOI: 10.1038/embor.2008.256[Crossref], [PubMed], [CAS], Google Scholar.71ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsVChsg%253D%253D&md5=8e67d5e63bdc6e84a3f7576cd6eaa74cRetroviral integrase superfamily: the structural perspectiveNowotny, MarcinEMBO Reports (2009), 10 (2), 144-151CODEN: ERMEAX; ISSN:1469-221X. (Nature Publishing Group)A review. The retroviral integrase superfamily (RISF) comprises numerous important nucleic acid-processing enzymes, including transposases, integrases and various nucleases. These enzymes are involved in a wide range of processes such as transposition, replication and repair of DNA, homologous recombination, and RNA-mediated gene silencing. Two out of the four enzymes that are encoded by the human immunodeficiency virus, RNase H1 and integrase, are members of this superfamily. RISF enzymes act on various substrates, and yet show remarkable mechanistic and structural similarities. All share a common fold of the catalytic core and the active site, which is composed primarily of carboxylate residues. Here, RISF proteins are presented from a structural perspective, describing the individual members and the common and divergent elements of their structures, as well as the mechanistic insights gained from the structures of RNase H1 enzyme complexes with RNA/DNA hybrids.(b) Majorek, K. A.; Dunin-Horkawicz, S.; Steczkiewicz, K.; Muszewska, A.; Nowotny, M.; Ginalski, K.; Bujnicki, J. M. The RNase H-like superfamily: new members, comparative structural analysis and evolutionary classification. Nucleic Acids Res. 2014, 42, 4160– 4179, DOI: 10.1093/nar/gkt1414[Crossref], [PubMed], [CAS], Google Scholar71bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXmtFSitLw%253D&md5=48cff800010a8087efcfcd1eca203ebcThe RNase H-like superfamily: new members, comparative structural analysis and evolutionary classificationMajorek, Karolina A.; Dunin-Horkawicz, Stanislaw; Steczkiewicz, Kamil; Muszewska, Anna; Nowotny, Marcin; Ginalski, Krzysztof; Bujnicki, Janusz M.Nucleic Acids Research (2014), 42 (7), 4160-4179CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)RNase H-like (RNHL) superfamily, also called the retroviral integrase superfamily, groups together numerous enzymes involved in nucleic acid metab. and implicated in many biol. processes, including replication, homologous recombination, DNA repair, transposition and RNA interference. The RNHL superfamily proteins show extensive divergence of sequences and structures. The authors conducted database searches to identify members of the RNHL superfamily (including those previously unknown), yielding >60 000 unique domain sequences. Their anal. led to the identification of new RNHL superfamily members, such as RRXRR (PF14239), DUF460 (PF04312, COG2433), DUF3010 (PF11215), DUF429 (PF04250 and COG2410, COG4328, COG4923), DUF1092 (PF06485), COG5558, OrfB_IS605 (PF01385, COG0675) and Peptidase_A17 (PF05380). Based on the clustering anal., the authors grouped all identified RNHL domain sequences into 152 families. Phylogenetic studies revealed relationships between these families, and suggested a possible history of the evolution of RNHL fold and its active site. The results revealed clear division of the RNHL superfamily into exonucleases and endonucleases. Structural analyses of features characteristic for particular groups revealed a correlation between the orientation of the C-terminal helix with the exonuclease/endonuclease function and the architecture of the active site. This anal. provides a comprehensive picture of sequence-structure-function relationships in the RNHL superfamily that may guide functional studies of the previously uncharacterized protein families.
- 72(a) Xu, P.; Ganaie, S. S.; Wang, X.; Wang, Z.; Kleiboeker, S.; Horton, N. C.; Heier, R. F.; Meyers, M. J.; Tavis, J. E.; Qiu, J. Endonuclease activity inhibition of the NS1 protein of parvovirus B19 as a novel target for antiviral drug development. Antimicrob. Agents Chemother. 2019, 63, AAC.01879, DOI: 10.1128/AAC.01879-18 .(b) Tavis, J. E.; Zoidis, G.; Meyers, M. J.; Murelli, R. P. Chemical approaches to inhibiting the hepatitis B virus ribonuclease H. ACS Infect. Dis. 2018, DOI: 10.1021/acsinfecdis.8b00045 .(c) Lomonosova, E.; Daw, J.; Garimallaprabhakaran, A. K.; Agyemang, N. B.; Ashani, Y.; Murelli, R. P.; Tavis, J. E. Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H. Antiviral Res. 2017, 144, 164– 172, DOI: 10.1016/j.antiviral.2017.06.014[Crossref], [PubMed], [CAS], Google Scholar.72chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVKntrjN&md5=b8f6cf6d2ba37d8d8d7bba073505e92eEfficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease HLomonosova, Elena; Daw, Jil; Garimallaprabhakaran, Aswin K.; Agyemang, Nana B.; Ashani, Yashkumar; Murelli, Ryan P.; Tavis, John E.Antiviral Research (2017), 144 (), 164-172CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral RNase H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α-hydroxytropolone compds. can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochem. RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity anal. of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.(d) Edwards, T. C.; Lomonosova, E.; Patel, J. A.; Li, Q.; Villa, J. A.; Gupta, A. K.; Morrison, L. A.; Bailly, F.; Cotelle, P.; Giannakopoulou, E.; Zoidis, G.; Tavis, J. E. Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles. Antiviral Res. 2017, 143, 205– 217, DOI: 10.1016/j.antiviral.2017.04.012[Crossref], [PubMed], [CAS], Google Scholar.72dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVaqtrk%253D&md5=3e1ded73ed62966b49f39182d38d00c4Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocyclesEdwards, Tiffany C.; Lomonosova, Elena; Patel, Jenny A.; Li, Qilan; Villa, Juan A.; Gupta, Ankit K.; Morrison, Lynda A.; Bailly, Fabrice; Cotelle, Philippe; Giannakopoulou, Erofili; Zoidis, Grigoris; Tavis, John E.Antiviral Research (2017), 143 (), 205-217CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)We previously reported low sensitivity of the hepatitis B virus (HBV) RNase H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compds. Subsequently, our biochem. RNaseH assay was found to have a high false neg. rate for predicting HBV replication inhibition, leading to underestimation of the no. of HIDs that inhibit HBV replication. Here, 39 HID compds. and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the pos.-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV pos.-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indexes from 2.4 to 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.(e) Lu, G.; Lomonosova, E.; Cheng, X.; Moran, E. A.; Meyers, M. J.; Le Grice, S. F.; Thomas, C. J.; Jiang, J. K.; Meck, C.; Hirsch, D. R.; D’Erasmo, M. P.; Suyabatmaz, D. M.; Murelli, R. P.; Tavis, J. E. Hydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activity. Antimicrob. Agents Chemother. 2015, 59, 1070– 1079, DOI: 10.1128/AAC.04617-14[Crossref], [PubMed], [CAS], Google Scholar.72ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXit1Kqsrg%253D&md5=ad57f43a17b6aaf4a68a5912a7e72c1eHydroxylated tropolones inhibit hepatitis B virus replication by blocking viral ribonuclease H activityLu, Gaofeng; Lomonosova, Elena; Cheng, Xiaohong; Moran, Eileen A.; Meyers, Marvin J.; Le Grice, Stuart F. J.; Thomas, Craig J.; Jiang, Jian-kang; Meck, Christine; Hirsch, Danielle R.; D'Erasmo, Michael P.; Suyabatmaz, Duygu M.; Murelli, Ryan P.; Tavis, John E.Antimicrobial Agents and Chemotherapy (2015), 59 (2), 1070-1079, 10 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compds. for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of detg. whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compds. inhibited HBV RNaseH, with the best 50% inhibitory concn. (IC50) being 2.3 μM. Similar inhibition patterns were obsd. against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compds. tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concn. (EC50) being 0.34 μM. Eighteen compds. inhibited recombinant human RNaseH1, and moderate cytotoxicity was obsd. for all compds. (50% cytotoxic concn. [CC50] = 25 to 79 μM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.(f) Cai, C. W.; Lomonosova, E.; Moran, E. A.; Cheng, X.; Patel, K. B.; Bailly, F.; Cotelle, P.; Meyers, M. J.; Tavis, J. E. Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity. Antiviral Res. 2014, 108, 48– 55, DOI: 10.1016/j.antiviral.2014.05.007[Crossref], [PubMed], [CAS], Google Scholar.72fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFGqsrnE&md5=790a7c0b6496897f62a68cbcfc747135Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activityCai, Catherine W.; Lomonosova, Elena; Moran, Eileen A.; Cheng, Xiaohong; Patel, Kunjan B.; Bailly, Fabrice; Cotelle, Philippe; Meyers, Marvin J.; Tavis, John E.Antiviral Research (2014), 108 (), 48-55CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Nucleos(t)ide analog drugs profoundly suppress Hepatitis B virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV RNase H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivs. for anti-HBV RNaseH activity. Nine compds. inhibited the HBV RNaseH, but activity was marginal for eight of them. Compd. #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1 μM and an EC50 of 4.2 μM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75 μM, yielding a therapeutic index of ∼18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metab. of the compd., or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure-activity relationships for the HBV and HIV RNaseHs. Therefore, HID compds. may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.(g) Hu, Y.; Cheng, X.; Cao, F.; Huang, A.; Tavis, J. E. β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activity. Antiviral Res. 2013, 99, 221– 229, DOI: 10.1016/j.antiviral.2013.06.007[Crossref], [PubMed], [CAS], Google Scholar.72ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFentrfI&md5=eef4048551eda1f278210bc4d68f9563β-Thujaplicinol inhibits hepatitis B virus replication by blocking the viral ribonuclease H activityHu, Yuan; Cheng, Xiaohong; Cao, Feng; Huang, Ailong; Tavis, John E.Antiviral Research (2013), 99 (3), 221-229CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Hepatitis B virus (HBV) is a hepatotropic DNA virus that replicates by reverse transcription. It chronically infects >350 million people and kills about 1 million patients annually. Therapy primarily employs nucleos(t)ide analogs that suppress viral DNA synthesis by the viral reverse transcriptase very well but that rarely cure the infection, so addnl. therapies are needed. Reverse transcription requires the viral RNase H (RNAseH) to destroy the viral RNA after it has been copied into DNA. We recently produced active recombinant HBV RNAseH and demonstrated that Human Immunodeficiency Virus (HIV) RNAseH antagonists could inhibit the HBV enzyme at a high frequency. Here, we extended these results to β-thujaplicinol, a hydroxylated tropolone which inhibits the HIV RNAseH. β-Thujaplicinol inhibited RNAseHs from HBV genotype D and H in biochem. assays with IC50 values of 5.9 ± 0.7 and 2.3 ± 1.7 μM, resp. It blocked replication of HBV genotypes A and D in culture by inhibiting the RNAseH activity with an estd. EC50 of ∼5 μM and a CC50 of 10.1 ± 1.7 μM. Activity of β-thujaplicinol against RNAseH sequences from multiple HBV genotypes implies that if chem. derivs. of β-thujaplicinol with improved efficacy and reduced toxicity can be identified, they would have promise as anti-HBV agents.(h) Tavis, J. E.; Cheng, X.; Hu, Y.; Totten, M.; Cao, F.; Michailidis, E.; Aurora, R.; Meyers, M. J.; Jacobsen, E. J.; Parniak, M. A.; Sarafianos, S. G. The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymes. PLoS Pathog. 2013, 9, e1003125, DOI: 10.1371/journal.ppat.1003125[Crossref], [PubMed], [CAS], Google Scholar.72hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXivVOrsbg%253D&md5=f7841946904e4fe9ae6cc7a7b4502de5The hepatitis B virus ribonuclease H is sensitive to inhibitors of the human immunodeficiency virus ribonuclease H and integrase enzymesTavis, John E.; Cheng, Xiaohong; Hu, Yuan; Totten, Michael; Cao, Feng; Michailidis, Eleftherios; Aurora, Rajeev; Meyers, Marvin J.; Jacobsen, E. Jon; Parniak, Michael A.; Sarafianos, Stefan G.PLoS Pathogens (2013), 9 (1), e1003125CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV RNase H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatog. HBV RNAseH activity in the enriched lysates was characterized in prepn. for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chem. structureactivity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compds. inhibited the HBV RNAseH at 10 μM, the best compds. had low micromolar IC50 values against the RNAseH and one compd. inhibited HBV replication in tissue culture at 10 μM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compds. developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development.(i) Ireland, P. J.; Tavis, J. E.; D’Erasmo, M. P.; Hirsch, D. R.; Murelli, R. P.; Cadiz, M. M.; Patel, B. S.; Gupta, A. K.; Edwards, T. C.; Korom, M.; Moran, E. A.; Morrison, L. A. Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex viruses. Antimicrob. Agents Chemother. 2016, 60, 2140– 2149, DOI: 10.1128/AAC.02675-15[Crossref], [PubMed], [CAS], Google Scholar72ihttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1WqtLrJ&md5=f836b99afbd3c106a54b3fbc2dc62d38Synthetic α-hydroxytropolones inhibit replication of wild-type and acyclovir-resistant herpes simplex virusesIreland, Peter J.; Tavis, John E.; D'Erasmo, Michael P.; Hirsch, Danielle R.; Murelli, Ryan P.; Cadiz, Mark M.; Patel, Bindi S.; Gupta, Ankit K.; Edwards, Tiffany C.; Korom, Maria; Moran, Eileen A.; Morrison, Lynda A.Antimicrobial Agents and Chemotherapy (2016), 60 (4), 2140-2149CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Herpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently detd. that certain natural troponoid compds. such as β-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic α-hydroxytropolones with the goals of detg. a preliminary structure-activity relationship for the α-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compds. inhibited HSV-1 and HSV-2 replication at 50 μM, and 10 compds. inhibited HSV-1 and HSV-2 at 5 μM, with similar inhibition patterns and potencies against both viruses being obsd. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concn. (EC50) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was obsd. for all compds. (50% cytotoxic concn. [CC50] of 50 to >100 μM). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically α-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.
- 73(a) Huber, A. D.; Michailidis, E.; Tang, J.; Puray-Chavez, M. N.; Boftsi, M.; Wolf, J. J.; Boschert, K. N.; Sheridan, M. A.; Leslie, M. D.; Kirby, K. A.; Singh, K.; Mitsuya, H.; Parniak, M. A.; Wang, Z.; Sarafianos, S. G. 3-Hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease H. Antimicrob. Agents Chemother. 2017, 61, e00245, DOI: 10.1128/AAC.00245-17[Crossref], [PubMed], [CAS], Google Scholar.73ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1SksrnL&md5=d519420e094913750925848d522fcdb93-Hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease HHuber, Andrew D.; Michailidis, Eleftherios; Tang, Jing; Puray-Chavez, Maritza N.; Boftsi, Maria; Wolf, Jennifer J.; Boschert, Kelsey N.; Sheridan, Megan A.; Leslie, Maxwell D.; Kirby, Karen A.; Singh, Kamalendra; Mitsuya, Hiroaki; Parniak, Michael A.; Wang, Zhengqiang; Sarafianos, Stefan G.Antimicrobial Agents and Chemotherapy (2017), 61 (6), e00245/1-e00245/5CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compds. inhibited HBV replication in the low micromolar range.(b) Wu, B.; Tang, J.; Wilson, D. J.; Huber, A. D.; Casey, M. C.; Ji, J.; Kankanala, J.; Xie, J.; Sarafianos, S. G.; Wang, Z. 3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides potently inhibit HIV-1 integrase and RNase H. J. Med. Chem. 2016, 59, 6136– 6148, DOI: 10.1021/acs.jmedchem.6b00040[ACS Full Text.], [CAS], Google Scholar73bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsFejs78%253D&md5=6914ec727a0308a1de9ec38f9db6134d3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase HWu, Bulan; Tang, Jing; Wilson, Daniel J.; Huber, Andrew D.; Casey, Mary C.; Ji, Juan; Kankanala, Jayakanth; Xie, Jiashu; Sarafianos, Stefan G.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (13), 6136-6148CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochem. testing and mol. modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogs also potently inhibited reverse transcriptase (RT) assocd. RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochem. properties suitable for further development.(c) Kankanala, J.; Kirby, K. A.; Liu, F.; Miller, L.; Nagy, E.; Wilson, D. J.; Parniak, M. A.; Sarafianos, S. G.; Wang, Z. Design, synthesis, and biological evaluations of hydroxypyridonecarboxylic acids as inhibitors of hiv reverse transcriptase associated RNase H. J. Med. Chem. 2016, 59, 5051– 5062, DOI: 10.1021/acs.jmedchem.6b00465[ACS Full Text.], [CAS], Google Scholar73chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XmsVams78%253D&md5=856a8a2c2d0c3c150ef845fb63db4e97Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase HKankanala, Jayakanth; Kirby, Karen A.; Liu, Feng; Miller, Lena; Nagy, Eva; Wilson, Daniel J.; Parniak, Michael A.; Sarafianos, Stefan G.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (10), 5051-5062CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeting the clin. unvalidated reverse transcriptase (RT) assocd. RNase H (RNase H) for human immunodeficiency virus (HIV) drug discovery generally entails chemotypes capable of chelating two divalent metal ions in the RNase H active site. The hydroxypyridonecarboxylic acid scaffold has been implicated in inhibiting homologous HIV integrase (IN) and influenza endonuclease via metal chelation. We report herein the design, synthesis, and biol. evaluations of a novel variant of the hydroxypyridonecarboxylic acid scaffold featuring a crucial N-1 benzyl or biarylmethyl moiety. Biochem. studies show that most analogs consistently inhibited HIV RT-assocd. RNase H in the low micromolar range in the absence of significant inhibition of RT polymerase or IN. Compd. I showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallog. studies corroborate favorable binding to the active site of HIV RNase H, providing a basis for the design of more potent analogs.(d) Tang, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Wu, B.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. 3-Hydroxypyrimidine-2,4-diones as selective active site inhibitors of hiv reverse transcriptase-associated RNase H: design, synthesis, and biochemical evaluations. J. Med. Chem. 2016, 59, 2648– 2659, DOI: 10.1021/acs.jmedchem.5b01879[ACS Full Text.], [CAS], Google Scholar73dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjsFaqtrg%253D&md5=906db68a78f7877f8bd8404227903dd83-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical EvaluationsTang, Jing; Liu, Feng; Nagy, Eva; Miller, Lena; Kirby, Karen A.; Wilson, Daniel J.; Wu, Bulan; Sarafianos, Stefan G.; Parniak, Michael A.; Wang, ZhengqiangJournal of Medicinal Chemistry (2016), 59 (6), 2648-2659CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human immunodeficiency virus (HIV) reverse transcriptase (RT) assocd. RNase H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochem. evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochem. studies showed the two subtypes with an N-1 Me group inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype, e.g., I, inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.(e) Wang, Y.; Tang, J.; Wang, Z.; Geraghty, R. J. Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication. Antiviral Res. 2018, 152, 10– 17, DOI: 10.1016/j.antiviral.2018.01.015[Crossref], [PubMed], [CAS], Google Scholar73ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXis1ansbw%253D&md5=fdd73309010aa57d6a7a835a10440b34Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replicationWang, Yan; Tang, Jing; Wang, Zhengqiang; Geraghty, Robert J.Antiviral Research (2018), 152 (), 10-17CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)Human cytomegalovirus terminase complex cleaves the concatemeric genomic viral DNA into unit lengths during genome packaging and particle assembly. Terminase complex ATPase and endonuclease activity is provided by the viral protein pUL89. pUL89 is an attractive drug target because its activities are required for infectious virus prodn. A domain located in the C-terminus of pUL89 has an RNase H/integrase-like fold and endonuclease activity that can be inhibited by compds. featuring a chelating triad motif. Previously, we developed a novel ELISA approach to screen for pUL89 inhibitors. In this report, we used the ELISA to identify 3-hydroxypyrimidine-2,4-dione as a promising scaffold for pUL89 inhibitor development. Several potent pUL89 inhibitors yielded low micromolar IC50 values in the enzymic assay and low micromolar EC50 values for inhibition of HCMV replication. Two representative compds. inhibitory effects depended upon metal ions and occurred late in virus replication consistent with pUL89 inhibitors in infected cells.
- 74(a) Sun, L.; Gao, P.; Dong, G.; Zhang, X.; Cheng, X.; Ding, X.; Wang, X.; Daelemans, D.; De Clercq, E.; Pannecouque, C.; Menéndez-Arias, L.; Zhan, P.; Liu, X. 5-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integrase. Eur. J. Med. Chem. 2018, 155, 714– 724, DOI: 10.1016/j.ejmech.2018.06.036[Crossref], [PubMed], [CAS], Google Scholar.74ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtF2qtbbF&md5=7b819ac0d1ba0d1a2dae8a1e3a7242755-Hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivatives as novel dual inhibitors of HIV-1 reverse transcriptase-associated ribonuclease H and integraseSun, Lin; Gao, Ping; Dong, Guanyu; Zhang, Xujie; Cheng, Xiqiang; Ding, Xiao; Wang, Xueshun; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Menendez-Arias, Luis; Zhan, Peng; Liu, XinyongEuropean Journal of Medicinal Chemistry (2018), 155 (), 714-724CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Herein the design, synthesis and biol. evaluation of a series of 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one derivs. I (R = 1-naphthyl, 1,1'-biphenyl, 4-(pyrimidin-5-yl)phenyl, etc.) as HIV-1 reverse transcriptase (RT) RNase H (RNase H) inhibitors using a privileged structure-guided scaffold refining strategy was reported. In view of the similarities between the pharmacophore model of RNase H and integrase (IN) inhibitors as well as their catalytic sites, IN inhibition assays was also performed. Notably, the majority of these derivs. inhibited RNase H and IN at micromolar concns. Among them, compd. I (R = 4'-cyano-[1,1'-biphenyl]) exhibited similar inhibitory activity against RNase H and IN (IC50RNase H = 1.77 μM, IC50IN = 1.18 μM, ratio = 1.50). To the best of knowledge, this is the first reported dual HIV-1 RNase H-IN inhibitor based on a 5-hydroxypyrido[2,3-b]pyrazin-6(5H)-one structure. Mol. modeling has been used to predict the binding mode of I (R = 4'-cyano-[1,1'-biphenyl]) in complex with the catalytic cores of HIV-1 RNase H and IN. Taken together these results strongly support the feasibility of developing HIV-1 dual inhibitors from analog-based optimization of divalent metal ion chelators. Recently, the identification of dual inhibitors proved to be a highly effective strategy for novel antivirals discovery. Therefore, these compds. appear to be useful leads that can be further modified to develop more valuable anti-HIV-1 mols. with suitable drug profiles.(b) Gao, P.; Zhang, L.; Sun, L.; Huang, T.; Tan, J.; Zhang, J.; Zhou, Z.; Zhao, T.; Menéndez-Arias, L.; Pannecouque, C.; Clercq, E.; Zhan, P.; Liu, X. 1-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound libraries. Bioorg. Med. Chem. 2017, 25, 5779– 5789, DOI: 10.1016/j.bmc.2017.09.006[Crossref], [PubMed], [CAS], Google Scholar.74bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGns7vJ&md5=1f5a9b575ef2004c9651850a0da2eaa31-Hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones as novel selective HIV integrase inhibitors obtained via privileged substructure-based compound librariesGao, Ping; Zhang, Lingzi; Sun, Lin; Huang, Tianguang; Tan, Jing; Zhang, Jian; Zhou, Zhongxia; Zhao, Tong; Menendez-Arias, Luis; Pannecouque, Christophe; Clercq, Erik De; Zhan, Peng; Liu, XinyongBioorganic & Medicinal Chemistry (2017), 25 (20), 5779-5789CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)A small library contg. 3-hydroxyquinazoline-2,4(1H,3H)-diones I (R = C6H5CH2, 4-FC6H4CH2, 2-CH3C6H4CH2, etc.) and 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones II (R1 = C6H5(CH2)2, naphthalene-1-yl, C6H5NHC(O)CH2, etc.), III (R2 = 4-FC6H4CH2, 4-CH3C6H4CH2) was obtained via the copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) reaction and evaluated for their anti-HIV activity in MT-4 cells. Among the synthesized compds., several 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-one derivs. II and III showed remarkable anti-HIV potency with EC50 values ranging from 0.92 to 26.85 μM. The most active one, II (R = 4-FC6H4CH2) also showed remarkable and selective potency against HIV type 1 integrase (IN). This is the first report showing that 1-hydroxypyrido[2,3-d]pyrimidin-2(1H)-ones II and III are selective HIV IN inhibitors. Preliminary structure-activity relationship (SAR) studies suggested that the divalent metal ion chelators and the nature and position of substituents around the core are important for antiviral potency. Mol. modeling has been used to predict the binding site of the pyrido[2,3-d]pyrimidin-2(1H)-one core in HIV type 1 IN and suggestions are made for improvement of its inhibitory activity.(c) Wang, X.; Gao, P.; Menendez-Arias, L.; Liu, X.; Zhan, P. Update on recent developments in small molecular hiv-1 rnase h inhibitors (2013–2016): opportunities and challenges. Curr. Med. Chem. 2018, 25, 1682– 1702, DOI: 10.2174/0929867324666170113110839[Crossref], [PubMed], [CAS], Google Scholar.74chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVWksr7L&md5=174f7026aa10084247e9d4968c7b8923Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013-2016): Opportunities and ChallengesWang, Xueshun; Gao, Ping; Menendez-Arias, Luis; Liu, Xinyong; Zhan, PengCurrent Medicinal Chemistry (2018), 25 (14), 1682-1702CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)Combinations of antiretroviral drugs are successfully used to treat HIV-infected patients. However, drug resistance is a major problem that makes discovery of new antiretroviral drugs an ongoing priority. The RNase H (RNase H) activity of the HIV-1 reverse transcriptase catalyzes the selective hydrolysis of the RNA strand of RNA:DNA heteroduplex replication intermediates, and represents an attractive unexploited target for drug development. This review reports on recent progress in the characterization of HIV-1 RNase H inhibitors from 2013 to 2016, describing their chem. structures, structureactivity relationship and binding modes. Focus is given to emerging medicinal chem. principles and insights into the discovery and development of RNase H inhibitors.(d) Cao, L.; Song, W.; De Clercq, E.; Zhan, P.; Liu, X. Recent progress in the research of small molecule HIV-1 RNase H inhibitors. Curr. Med. Chem. 2014, 21, 1956– 1967, DOI: 10.2174/0929867321666140120121158[Crossref], [PubMed], [CAS], Google Scholar.74dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnt1emt78%253D&md5=b304a792478d2ffcbe8d85405c74f0c1Recent Progress in the Research of Small Molecule HIV-1 RNase H InhibitorsCao, Lili; Song, Weiguo; De Clercq, Erik; Zhan, Peng; Liu, XinyongCurrent Medicinal Chemistry (2014), 21 (17), 1956-1967CODEN: CMCHE7; ISSN:0929-8673. (Bentham Science Publishers Ltd.)A review. Reverse transcription of human immunodeficiency virus type 1 (HIV-1) is a crucial step in the life cycle initiated by the viral-coded reverse transcriptase (RT), functioning as RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the RNase H (RNase H). The RNase H functions to degrade the RNA strand of the RNA:DNA heteroduplex, which makes it an attractive target for rational anti-HIV-1 drug design and development. Although development of drugs targeting the DNA polymerase have been highly successful, the discovery of drugable inhibitors of HIV RNase H is still in its infancy and none of RNase H inhibitors has reached the clin. development stage currently. This review describes the recent progress in the HIV-1 RNase H inhibitors, focusing on their chem. feature, mechanism and the structure-activity relationship (SAR).(e) Ju, H.; Zhang, J.; Huang, B.; Kang, D.; Huang, B.; Liu, X.; Zhan, P. Inhibitors of influenza virus polymerase acidic (PA) endonuclease: contemporary developments and perspectives. J. Med. Chem. 2017, 60, 3533– 3551, DOI: 10.1021/acs.jmedchem.6b01227[ACS Full Text.], [CAS], Google Scholar74ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFajs7Y%253D&md5=0432281c788ab6844753668e8208c3f6Inhibitors of Influenza Virus Polymerase Acidic (PA) Endonuclease: Contemporary Developments and PerspectivesJu, Han; Zhang, Jian; Huang, Boshi; Kang, Dongwei; Huang, Bing; Liu, Xinyong; Zhan, PengJournal of Medicinal Chemistry (2017), 60 (9), 3533-3551CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Influenza virus (IFV) causes periodic global influenza pandemics, resulting in substantial socio-economic loss and burden on medical facilities. Yearly variation in the effectiveness of vaccines, slow responsiveness to vaccination in cases of pandemic IFV, and emerging resistance to available drugs highlight the need to develop addnl. small-mol. inhibitors that act on IFV proteins. One promising target is polymerase acidic (PA) endonuclease, which is a bridged dinuclear metalloenzyme that plays a crucial role in initiating IFV replication. During the past decade, intensive efforts have been made to develop small-mol. inhibitors of this endonuclease as candidate agents for treatment of IFV infection. Here, the authors review the current status of development of PA endonuclease inhibitors and the authors discuss the applicability of newer medicinal-chem. strategies for the discovery more potent, selective, and safer inhibitors.(f) Ju, H.; Zhan, P.; Liu, X. Designing influenza polymerase acidic endonuclease inhibitors via ’privileged scaffold’ re-evolution/refining strategy. Future Med. Chem. 2019, 11, 265, DOI: 10.4155/fmc-2018-0489[Crossref], [CAS], Google Scholar74fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtlKhuro%253D&md5=4561c54e9850070aa333d4380cc0dbb9Designing influenza polymerase acidic endonuclease inhibitors via 'privileged scaffold' re-evolution/refining strategyJu, Han; Zhan, Peng; Liu, XinyongFuture Medicinal Chemistry (2019), 11 (4), 265-268CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review discussing the design of influenza polymerase acidic endonuclease inhibitors via privileged scaffold re-evolution/refining strategy.
- 75Yang, T. Baloxavir Marboxil: The first cap-dependent endonuclease inhibitor for the treatment of influenza. Ann. Pharmacother. 2019, 106002801982656, DOI: 10.1177/1060028019826565
- 76Oh, S.; Park, Y.; Engelhart, C. A.; Wallach, J. B.; Schnappinger, D.; Arora, K.; Manikkam, M.; Gac, B.; Wang, H.; Murgolo, N.; Olsen, D. B.; Goodwin, M.; Sutphin, M.; Weiner, D. M.; Via, L. E.; Boshoff, H. I. M.; Barry, C. E., 3rd. Discovery and structure-activity-relationship study of n-alkyl-5-hydroxypyrimidinone carboxamides as novel antitubercular agents targeting decaprenylphosphoryl-β-d-ribose 2′-oxidase. J. Med. Chem. 2018, 61, 9952– 9965, DOI: 10.1021/acs.jmedchem.8b00883[ACS Full Text], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2rsrfP&md5=5c8f50d73f857fcde7277ca80109fee9Discovery and Structure-Activity-Relationship Study of N-Alkyl-5-hydroxypyrimidinone Carboxamides as Novel Antitubercular Agents Targeting Decaprenylphosphoryl-β-D-ribose 2'-OxidaseOh, Sangmi; Park, Yumi; Engelhart, Curtis A.; Wallach, Joshua B.; Schnappinger, Dirk; Arora, Kriti; Manikkam, Michelle; Gac, Brian; Wang, Hongwu; Murgolo, Nicholas; Olsen, David B.; Goodwin, Michael; Sutphin, Michelle; Weiner, Danielle M.; Via, Laura E.; Boshoff, Helena I. M.; Barry, Clifton E.Journal of Medicinal Chemistry (2018), 61 (22), 9952-9965CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Magnesium plays an important role in infection with Mycobacterium tuberculosis (Mtb) as a signal of the extracellular environment, as a cofactor for many enzymes, and as a structural element in important macromols. Raltegravir, an antiretroviral drug that inhibits HIV-1 integrase is known to derive its potency from selective sequestration of active-site magnesium ions in addn. to binding to a hydrophobic pocket. In order to det. if essential Mtb-related phosphoryl transfers could be disrupted in a similar manner, a directed screen of known mols. with integrase inhibitor-like pharmacophores (N-alkyl-5-hydroxypyrimidinone carboxamides) was performed. Initial hits afforded compds. with low-micromolar potency against Mtb, acceptable cytotoxicity and PK characteristics, and robust SAR. Elucidation of the target of these compds. revealed that they lacked magnesium dependence and instead disappointingly inhibited a known promiscuous target in Mtb, decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1, Rv3790).
- 77Ramil, C. P.; Lin, Q. Bioorthogonal chemistry: strategies and recent developments. Chem. Commun. (Cambridge, U. K.) 2013, 49, 11007– 11022, DOI: 10.1039/c3cc44272a[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslWls7vL&md5=55e8bcb626cf7d28ea9937a8fe800ca8Bioorthogonal chemistry: strategies and recent developmentsRamil, Carlo P.; Lin, QingChemical Communications (Cambridge, United Kingdom) (2013), 49 (94), 11007-11022CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. The use of covalent chem. to track biomols. in their native environment-a focus of bioorthogonal chem.-has received considerable interest recently among chem. biologists and org. chemists alike. To facilitate wider adoption of bioorthogonal chem. in biomedical research, a central effort in the last few years has been focused on the optimization of a few known bioorthogonal reactions, particularly with respect to reaction kinetics improvement, novel genetic encoding systems, and fluorogenic reactions for bioimaging. During these optimizations, three strategies have emerged, including the use of ring strain for substrate activation in the cycloaddn. reactions, the discovery of new ligands and privileged substrates for accelerated metal-catalyzed reactions, and the design of substrates with pre-fluorophore structures for rapid "turn-on" fluorescence after selective bioorthogonal reactions. In addn., new bioorthogonal reactions based on either modified or completely unprecedented reactant pairs have been reported. Finally, increasing attention has been directed toward the development of mutually exclusive bioorthogonal reactions and their applications in multiple labeling of a biomol. in cell culture. In this feature article, the authors wish to present the recent progress in bioorthogonal reactions through the selected examples that highlight the above-mentioned strategies. Considering increasing sophistication in bioorthogonal chem. development, the authors strive to project several exciting opportunities where bioorthogonal chem. can make a unique contribution to biol. in the near future.
- 78Kim, J.; Kim, H.; Park, S. B. Privileged structures: efficient chemical ″navigators″ toward unexplored biologically relevant chemical spaces. J. Am. Chem. Soc. 2014, 136, 14629– 14638, DOI: 10.1021/ja508343a[ACS Full Text], [CAS], Google Scholar78https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsleksrjM&md5=27672b927e95b898a7f95cb0f2bd1ef8Privileged Structures: Efficient Chemical "Navigators" toward Unexplored Biologically Relevant Chemical SpacesKim, Jonghoon; Kim, Heejun; Park, Seung BumJournal of the American Chemical Society (2014), 136 (42), 14629-14638CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A review. In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally "undruggable" targets, and collections of drug-like small mols. with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chem. space with drug-like compds. contg. a high degree of mol. diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small mols. and therapeutic agents, and thus DOS has emerged as an essential tool in chem. biol. and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-mol. libraries with improved biol. relevancy as well as max. mol. diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compd. libraries with high biol. relevancy. We envisioned the specific interaction of drug-like small mols. with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small mols. and the subsequent identification of appropriate target biomol. using a method called "fluorescence difference in two-dimensional gel electrophoresis". Focusing on examples of pDOS-derived bioactive compds. with exceptional specificity, we discuss the capability of privileged structures to serve as chem. "navigators" toward biol. relevant chem. spaces. We also provide an outlook on chem. biol. research and drug discovery using biol. relevant compd. libraries constructed by pDOS, biol.-oriented synthesis, or natural product-inspired DOS.
- 79(a) Wang, X.; Huang, B.; Liu, X.; Zhan, P. Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial libraries. Drug Discovery Today 2016, 21, 118– 132, DOI: 10.1016/j.drudis.2015.08.004[Crossref], [PubMed], [CAS], Google Scholar.79ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVOnt7%252FN&md5=57314fbcbf2e16e2267a8c9513a39b13Discovery of bioactive molecules from CuAAC click-chemistry-based combinatorial librariesWang, Xueshun; Huang, Boshi; Liu, Xinyong; Zhan, PengDrug Discovery Today (2016), 21 (1), 118-132CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)The rapid assembly and in situ screening of focused combinatorial fragment libraries using CuAAC click chem. is a highly robust and efficient strategy for establishing SAR and for discovering bioactive mols. This review outlines the current status of this methodol. in drug discovery application. The inherent limitations, challenges and prospects are critically discussed.(b) Huang, B.; Kang, D.; Zhan, P.; Liu, X. Fragment-based approaches to anti-HIV drug discovery: state of the art and future opportunities. Expert Opin. Drug Discovery 2015, 10, 1271– 1281, DOI: 10.1517/17460441.2015.1083007[Crossref], [PubMed], [CAS], Google Scholar.79bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFOmt7fK&md5=dc7627df6061a44e0595c1609094414dFragment-based approaches to anti-HIV drug discovery: state of the art and future opportunitiesHuang, Boshi; Kang, Dongwei; Zhan, Peng; Liu, XinyongExpert Opinion on Drug Discovery (2015), 10 (12), 1271-1281CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)The search for addnl. drugs to treat HIV infection is a continuing effort due to the emergence and spread of HIV strains resistant to nearly all current drugs. The recent literature reveals that fragment-based drug design/discovery (FBDD) has become an effective alternative to conventional high-throughput screening strategies for drug discovery. In this crit. review, the authors describe the state of the art in FBDD strategies for the discovery of anti-HIV drug-like compds. The article focuses on fragment screening techniques, direct fragment-based design and early hit-to-lead progress. Rapid progress in biophys. detection and in silico techniques has greatly aided the application of FBDD to discover candidate agents directed at a variety of anti-HIV targets. Growing evidence suggests that structural insights on key proteins in the HIV life cycle can be applied in the early phase of drug discovery campaigns, providing valuable information on the binding modes and efficiently prompting fragment hit-to-lead progression. The combination of structural insights with improved methodologies for FBDD, including the privileged fragment-based reconstruction approach, fragment hybridization based on crystallog. overlays, fragment growth exploiting dynamic combinatorial chem., and high-speed fragment assembly via diversity-oriented synthesis followed by in situ screening, offers the possibility of more efficient and rapid discovery of novel drugs for HIV-1 prevention or treatment. Though the use of FBDD in anti-HIV drug discovery is still in its infancy, it is anticipated that anti-HIV agents developed via fragment-based strategies will be introduced into the clinic in the future.(c) Gao, P.; Sun, L.; Zhou, J.; Li, X.; Zhan, P.; Liu, X. Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approach. Expert Opin. Drug Discovery 2016, 11, 857– 871, DOI: 10.1080/17460441.2016.1210125[Crossref], [PubMed], [CAS], Google Scholar79chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1ejtbfK&md5=bfd4b8346b9b38bf68f3fcbba1f198b4Discovery of novel anti-HIV agents via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry-based approachGao, Ping; Sun, Lin; Zhou, Junsu; Li, Xiao; Zhan, Peng; Liu, XinyongExpert Opinion on Drug Discovery (2016), 11 (9), 857-871CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)In recent years, a variety of new synthetic methodologies and concepts have been proposed in the search for new pharmaceutical lead structures and optimization. Notably, the Cu(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) click chem. approach has drawn great attention and has become a powerful tool for the generation of privileged medicinal skeletons in the discovery of anti-HIV agents. This is due to the high degree of reliability, complete specificity (chemoselectivity and regioselectivity), mild conditions, and the biocompatibility of the reactants.: Herein, the authors describe the progress thus far on the discovery of novel anti-HIV agents via the CuAAC click chem.-based approach.: CuAAC click chem. is a proven protocol for synthesizing triazole products which could serve as basic pharmacophores, act as replacements of traditional scaffold or substituent modification, be a linker of dual-target or dual-site inhibitors and more for the discovery of novel anti-HIV agents. What's more, it also provides convenience and feasibility for dynamic combinatorial chem. and in situ screening. It is envisioned that click chem. will draw more attention and make more contributions in anti-HIV drug discovery in the future.
- 80Whiting, M.; Tripp, J. C.; Lin, Y. C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless, K. B.; Fokin, V. V. Rapid discovery and structure-activity profiling of novel inhibitors of human immunodeficiency virus type 1 protease enabled by the copper(I)-catalyzed synthesis of 1,2,3-triazoles and their further functionalization. J. Med. Chem. 2006, 49, 7697– 7710, DOI: 10.1021/jm060754+[ACS Full Text], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xht1GjsbjL&md5=252fb639055fb8e55a1e1a0eb0842853Rapid Discovery and Structure-Activity Profiling of Novel Inhibitors of Human Immunodeficiency Virus Type 1 Protease Enabled by the Copper(I)-Catalyzed Synthesis of 1,2,3-Triazoles and Their Further FunctionalizationWhiting, Matthew; Tripp, Jonathan C.; Lin, Ying-Chuan; Lindstrom, William; Olson, Arthur J.; Elder, John H.; Sharpless, K. Barry; Fokin, Valery V.Journal of Medicinal Chemistry (2006), 49 (26), 7697-7710CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Building from the results of a computational screen of a range of triazole-contg. compds. for binding efficiency to human immunodeficiency virus type 1 protease (HIV-1-Pr), a novel series of potent inhibitors has been developed. The copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC), which provides ready access to 1,4-disubstituted-1,2,3-triazoles, was used to unite a focused library of azide-contg. fragments with a diverse array of functionalized alkyne-contg. building blocks. In combination with direct screening of the crude reaction products, this method led to the rapid identification of a lead structure and readily enabled optimization of both azide and alkyne fragments. Replacement of the triazole with a range of alternative linkers led to greatly reduced protease inhibition; however, further functionalization of the triazoles at the 5-position gave a series of compds. with increased activity, exhibiting Ki values as low as 8 nM.
- 81(a) Zhan, P.; Wang, X.; Liu, X.; Suzuki, T. Medicinal chemistry insights into novel HDAC inhibitors: an updated patent review (2012–2016). Recent Pat. Anti-Cancer Drug Discovery 2017, 12, 16– 34, DOI: 10.2174/1574892811666161101102842[Crossref], [PubMed], [CAS], Google Scholar.81ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1eqs7o%253D&md5=3b9f5e1eb3ad18be92e438952fb06efcMedicinal Chemistry Insights into Novel HDAC Inhibitors: An Updated Patent Review (2012-2016)Zhan, Peng; Wang, Xueshun; Liu, Xinyong; Suzuki, TakayoshiRecent Patents on Anti-Cancer Drug Discovery (2017), 12 (1), 16-34CODEN: RPADDY; ISSN:1574-8928. (Bentham Science Publishers Ltd.)A review. Background: Many labs. have made intensive efforts to develop potent, selective, and orally bioavailable HDAC inhibitors (HDACIs). Novel HDACIs are being developed with the objective of improving potency and selectivity against specific types of cancers or non-cancer diseases. Objective: This updated patent review is an attempt to compile the work of various researchers of HDACIs from 2012 to mid 2016, and to enlighten and surprise both newcomers in this field and devoted medicinal chemists. Method: According to the literature research and the writers' own research experience in the discovery of HDAC inhibitors. Results: The inhibitors possessing new chem. scaffolds have attracted immense interest because they have the ability to improve HDAC isoform specificity and pharmaceutical properties. Focus is given to emerging medicinal chem. principles and insights into the discovery and development of HDAC inhibitors. Conclusion: The development of effective HDACIs is shifting from trial-and-error approaches to sophisticated strategies. Effective profiling technologies will continue to have important utility.(b) Suzuki, T.; Ota, Y.; Ri, M.; Bando, M.; Gotoh, A.; Itoh, Y.; Tsumoto, H.; Tatum, P. R.; Mizukami, T.; Nakagawa, H.; Iida, S.; Ueda, R.; Shirahige, K.; Miyata, N. Rapid discovery of highly potent and selective inhibitors of histone deacetylase 8 using click chemistry to generate candidate libraries. J. Med. Chem. 2012, 55, 9562– 9575, DOI: 10.1021/jm300837y[ACS Full Text.], [CAS], Google Scholar81bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsF2qtrfI&md5=9b730c0469b62c3ebd93a5e58c520a12Rapid Discovery of Highly Potent and Selective Inhibitors of Histone Deacetylase 8 Using Click Chemistry to Generate Candidate LibrariesSuzuki, Takayoshi; Ota, Yosuke; Ri, Masaki; Bando, Masashige; Gotoh, Aogu; Itoh, Yukihiro; Tsumoto, Hiroki; Tatum, Prima R.; Mizukami, Tamio; Nakagawa, Hidehiko; Iida, Shinsuke; Ueda, Ryuzo; Shirahige, Katsuhiko; Miyata, NaokiJournal of Medicinal Chemistry (2012), 55 (22), 9562-9575CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To find HDAC8-selective inhibitors, we designed a library of HDAC inhibitor candidates, each contg. a zinc-binding group that coordinates with the active-site zinc ion, linked via a triazole moiety to a capping structure that interacts with residues on the rim of the active site. These compds. were synthesized by using click chem. Screening identified HDAC8-selective inhibitors including (I) (IC50 = 0.070 μM), which was more potent than PCI-34058 (IC50 = 0.31 μM), a known HDAC8 inhibitor. Mol. modeling suggested that the phenylthiomethyl group of I binds to a unique hydrophobic pocket of HDAC8, and the orientation of the phenylthiomethyl and hydroxamate moieties (fixed by the triazole moiety) is important for the potency and selectivity. The inhibitors caused selective acetylation of cohesin in cells and exerted growth-inhibitory effects on T-cell lymphoma and neuroblastoma cells (GI50 = 3-80 μM). These findings suggest that HDAC8-selective inhibitors have potential as anticancer agents.(c) Suzuki, T.; Kasuya, Y.; Itoh, Y.; Ota, Y.; Zhan, P.; Asamitsu, K.; Nakagawa, H.; Okamoto, T.; Miyata, N. Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. PLoS One 2013, 8, e68669, DOI: 10.1371/journal.pone.0068669[Crossref], [PubMed], [CAS], Google Scholar.81chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SgsrjF&md5=74d12c8fb1f06f8e00691415434fd929Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assemblySuzuki, Takayoshi; Kasuya, Yuki; Itoh, Yukihiro; Ota, Yosuke; Zhan, Peng; Asamitsu, Kaori; Nakagawa, Hidehiko; Okamoto, Takashi; Miyata, NaokiPLoS One (2013), 8 (7), e68669CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chem.", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isoenzymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compds. showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isoenzymes. Compds. T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addn., these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chem. approach to find isoenzyme-selective HDAC inhibitors.(d) Tatum, P. R.; Sawada, H.; Ota, Y.; Itoh, Y.; Zhan, P.; Ieda, N.; Nakagawa, H.; Miyata, N.; Suzuki, T. Identification of novel SIRT2-selective inhibitors using a click chemistry approach. Bioorg. Med. Chem. Lett. 2014, 24, 1871– 1874, DOI: 10.1016/j.bmcl.2014.03.026[Crossref], [PubMed], [CAS], Google Scholar81dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltFKms7s%253D&md5=59676924d20f19655d23b39f4799769aIdentification of novel SIRT2-selective inhibitors using a click chemistry approachTatum, Prima R.; Sawada, Hideyuki; Ota, Yosuke; Itoh, Yukihiro; Zhan, Peng; Ieda, Naoya; Nakagawa, Hidehiko; Miyata, Naoki; Suzuki, TakayoshiBioorganic & Medicinal Chemistry Letters (2014), 24 (8), 1871-1874CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of 114 SIRT inhibitor candidates was assembled using 'click chem.', by reacting two alkynes bearing 2-anilinobenzamide pharmacophore with 57 azide building blocks in the presence of Cu(I) catalyst. Screening identified two SIRT2-selective inhibitors, which were more SIRT2-selective than AGK2, a known SIRT2 inhibitor. These findings will be useful for further development of SIRT2-selective inhibitors.
- 82Gehringer, M.; Forster, M.; Laufer, S. A. Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition. ACS Comb. Sci. 2015, 17, 5– 10, DOI: 10.1021/co500122h[ACS Full Text], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvFCisbnI&md5=5d2999fedb2dfef332c2e860a9e376e4Solution-Phase Parallel Synthesis of Ruxolitinib-Derived Janus Kinase Inhibitors via Copper-Catalyzed Azide-Alkyne CycloadditionGehringer, Matthias; Forster, Michael; Laufer, Stefan A.ACS Combinatorial Science (2015), 17 (1), 5-10CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)A soln.-phase parallel synthesis of triazole-derived ruxolitinib analogs, e.g. I, was developed in the current study. The method employs copper-catalyzed azide-alkyne cycloaddn. to build up the central triazole template. Product isolation by pptn. and centrifugation is straightforward and yields high purity compds. suited for biol. profiling. A simple protocol for accessing the terminal alkyne precursors in high yields was established and a library of ruxolitinib-like triazoles featuring diverse functional groups was prepd. In addn., a model for the binding mode of ruxolitinib to Janus kinase (JAK) 2 is proposed. In contrast to previous models, the pose explains the compd. selectivity for JAK1/JAK2 and is in accordance with published structure-activity data. On this basis, a structure-based design hypothesis for inverting the selectivity profile of ruxolitinib is deduced. Application of this strategy identified a moderately potent JAK3 inhibitor (35 nM) with high selectivity against other JAKs, potentially exploiting a covalent binding mode.
- 83Diaz, L.; Casas, J.; Bujons, J.; Llebaria, A.; Delgado, A. New glucocerebrosidase inhibitors by exploration of chemical diversity of N-substituted aminocyclitols using click chemistry and in situ screening. J. Med. Chem. 2011, 54, 2069– 2079, DOI: 10.1021/jm101204u[ACS Full Text], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXislGmtbw%253D&md5=f8dc841b74e119008201a1142cb7175aNew Glucocerebrosidase Inhibitors by Exploration of Chemical Diversity of N-Substituted Aminocyclitols Using Click Chemistry and in Situ ScreeningDiaz, Lucia; Casas, Josefina; Bujons, Jordi; Llebaria, Amadeu; Delgado, AntonioJournal of Medicinal Chemistry (2011), 54 (7), 2069-2079CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A library of aminocyclitols, e.g. I, derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to phys. and reactivity constraints. A synthetic methodol. has been optimized in order to avoid the use of protecting groups on the aminocyclitol scaffold. Because the reaction can be carried out in an aq. system, the resulting library members can be screened in situ with minimal manipulation. From the preliminary GCase inhibition data, the most potent library members have been individually re-synthesized for further biol. screening and complete characterization. Some of the library members have shown biochem. data (IC50, Ki, and stabilization ratio) similar or superior to those reported for NNDNJ. Docking studies have been used to postulate ligand-enzyme interactions to account for the exptl. results.
- 84Coumar, M. S.; Chu, C. Y.; Lin, C. W.; Shiao, H. Y.; Ho, Y. L.; Reddy, R.; Lin, W. H.; Chen, C. H.; Peng, Y. H.; Leou, J. S.; Lien, T. W.; Huang, C. T.; Fang, M. Y.; Wu, S. H.; Wu, J. S.; Chittimalla, S. K.; Song, J. S.; Hsu, J. T.; Wu, S. Y.; Liao, C. C.; Chao, Y. S.; Hsieh, H. P. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. J. Med. Chem. 2010, 53, 4980– 4988, DOI: 10.1021/jm1000198[ACS Full Text], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnsFyhs7s%253D&md5=8064e99d8d31603c7186b5fa33e019a6Fast-Forwarding Hit to Lead: Aurora and Epidermal Growth Factor Receptor Kinase Inhibitor Lead IdentificationCoumar, Mohane Selvaraj; Chu, Chang-Ying; Lin, Cheng-Wei; Shiao, Hui-Yi; Ho, Yun-Lung; Reddy, Randheer; Lin, Wen-Hsing; Chen, Chun-Hwa; Peng, Yi-Hui; Leou, Jiun-Shyang; Lien, Tzu-Wen; Huang, Chin-Ting; Fang, Ming-Yu; Wu, Szu-Huei; Wu, Jian-Sung; Chittimalla, Santhosh Kumar; Song, Jen-Shin; Hsu, John T.-A.; Wu, Su-Ying; Liao, Chun-Chen; Chao, Yu-Sheng; Hsieh, Hsing-PangJournal of Medicinal Chemistry (2010), 53 (13), 4980-4988CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Furanopyrimidines such as I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4] are prepd. as Aurora A kinase and epidermal growth factor receptor (EGFR) inhibitors by prepn. of a combinatorial library of approx. 350 furanopyridines and optimization of the inhibitors found from the library. The initial hit compd. I (R = HOCH2CH2; R1 = Ph) was modified to better fit the back pocket to produce the potent Aurora A kinase inhibitor I (R = 4-PhNHCONHC6H4; R1 = Ph) with submicromolar antiproliferative activity in the HCT-116 human colon cancer cell line. On the basis of docking studies with EGFR hit I [R = (S)-HOCH2CHPh; R1 = Ph], introduction of an acrylamide Michael acceptor group led to I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4], which inhibited both the wild and mutant EGFR kinases and also showed antiproliferative activity in the gefitinib-resistant HCC827 human lung cancer cells. The X-ray cocrystal structures of I (R = HOCH2CH2, 4-PhNHCONHC6H4; R1 = Ph) bound to Aurora A kinase and the crystal structure of I [R = (S)-HOCH2CHPh; R1 = 3-(H2C:CCONH)C6H4] bound to EGFR confirmed their hypothesized binding modes.
- 85Ding, S.; Qiao, X.; Kucera, G. L.; Bierbach, U. Using a build-and-click approach for producing structural and functional diversity in DNA-targeted hybrid anticancer agents. J. Med. Chem. 2012, 55, 10198– 10203, DOI: 10.1021/jm301278c[ACS Full Text], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFamtr3E&md5=0ec806d4a18c7d19356f3384da200f92Using a Build-and-Click Approach for Producing Structural and Functional Diversity in DNA-Targeted Hybrid Anticancer AgentsDing, Song; Qiao, Xin; Kucera, Gregory L.; Bierbach, UlrichJournal of Medicinal Chemistry (2012), 55 (22), 10198-10203CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)An efficient screening method was developed for functionalized DNA-targeted Pt-contg. hybrid anticancer agents based on metal-mediated amine-to-nitrile addn., a form of click chem. The goal of the study was to generate Pt-acridine agents for their use as cytotoxic warheads in targeted and multifunctional therapies. This was achieved by introducing hydroxyl, carboxylic acid, and azide functionalities in the acridine linker moiety and by varying the nonleaving groups attached to Pt. The assay, which was based on microscale reactions between 6 Pt-nitrile complexes and 10 acridine derivs., yielded a small library of 60 Pt-acridines. Reactions were monitored, and product mixts. were quant. analyzed by automated in-line HPLC-electrospray mass spectrometry (LC-ESMS) anal. and subjected to cell viability screening (NCI-H460 cells) using a nonradioactive cell proliferation assay. The new prescreening methodol. proves to be a powerful tool for establishing structure-activity relations and for identifying target compds.
- 86Akgun, B.; Hall, D. G. Fast and tight boronate formation for click bioorthogonal conjugation. Angew. Chem., Int. Ed. 2016, 55, 3909– 3913, DOI: 10.1002/anie.201510321[Crossref], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XjtlKgsLY%253D&md5=35b91b335c735d76e135ede920db1807Fast and Tight Boronate Formation for Click Bioorthogonal ConjugationAkgun, Burcin; Hall, Dennis G.Angewandte Chemie, International Edition (2016), 55 (12), 3909-3913CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A new click bioorthogonal reaction system was devised to enable the fast ligation (kON ≈ 340 M-1 s-1) of conjugatable derivs. of a rigid cyclic diol (nopoldiol) and a carefully optimized boronic acid partner, 2-methyl-5-carboxymethylphenylboronic acid. Using NMR and fluorescence spectroscopy studies, the corresponding boronates form reversibly within minutes at low micromolar concn. in water, providing submicromolar equil. const. (Keq≈105-106 M-1). Efficient protein conjugation under physiol. conditions was demonstrated with model proteins thioredoxin and albumin, and characterized by mass spectrometry and gel electrophoresis.
- 87Oueis, E.; Sabot, C.; Renard, P. Y. New insights into the kinetic target-guided synthesis of protein ligands. Chem. Commun. (Cambridge, U. K.) 2015, 51, 12158– 12169, DOI: 10.1039/C5CC04183J[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFWgtbbE&md5=76af69545c88c006feb0fe7a544b3805New insights into the kinetic target-guided synthesis of protein ligandsOueis, Emilia; Sabot, Cyrille; Renard, Pierre-YvesChemical Communications (Cambridge, United Kingdom) (2015), 51 (61), 12158-12169CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A review. The kinetic target-guided synthesis (KTGS) strategy is an unconventional discovery approach that takes advantage of the presence of the biol. target itself in order to irreversibly assemble the best inhibitors from an array of building blocks. This strategy has grown over the last two decades notably after the introduction of the in situ click chem. concept by Sharpless and colleagues in the early 2000s based on the use of the Huisgen cycloaddn. between terminal alkynes and azides. KTGS is a captivating area of research offering an unprecedented and powerful strategy to probe the macromol. complexity and dynamics of biol. targets. After a brief introduction listing all chem. ligation reactions reported to date in KTGS, this review focuses on the last five years' progress to expand the repertoire of the click or "click-like" tool box targeting proteins, as well as to overcome limitations arising in particular from false negatives, i.e. potent ligands that are not formed, or formed in undetectable trace amts. Furthermore, we wish to analyze the new twists and novelties described in some of these applications in order to better understand the conditions that govern this strategy and the extent to which it can be developed and generalized for a more efficient process.
- 88Frei, P.; Hevey, R.; Ernst, B. Dynamic combinatorial chemistry: A new methodology comes of age. Chemistry 2019, 25, 60, DOI: 10.1002/chem.201803365[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKqtL%252FF&md5=7943caf1b6063ab321b0543282c2e526Dynamic Combinatorial Chemistry: A New Methodology Comes of AgeFrei, Priska; Hevey, Rachel; Ernst, BeatChemistry - A European Journal (2019), 25 (1), 60-73CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Dynamic combinatorial chem. (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromol. targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodn. equil. However, upon addn. of a macromol. host which can bind and stabilize certain components of the library, the equil. compn. changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacol. relevant targets. Over time, the term tdDCC has been applied to describe a no. of different exptl. setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for anal. and evaluation of expts.
- 89Unver, M. Y.; Gierse, R. M.; Ritchie, H.; Hirsch, A. K. H. Druggability assessment of targets used in kinetic target-guided synthesis. J. Med. Chem. 2018, 61, 9395– 9409, DOI: 10.1021/acs.jmedchem.8b00266[ACS Full Text], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVOmsLzO&md5=7f39f01bbc696d2f3bf27dc1d41c1bf4Druggability Assessment of Targets Used in Kinetic Target-Guided SynthesisUnver, M. Yagiz; Gierse, Robin M.; Ritchie, Harry; Hirsch, Anna K. H.Journal of Medicinal Chemistry (2018), 61 (21), 9395-9409CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biol. target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biol. target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, the authors performed a druggability assessment for each target family reported in KTGS, calcd. detailed information about the pocket properties and used them to search for possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall the authors conclude that the KTGS approach is universal and could be used without restrictions on the physicochem. properties of the addressed pocket.
- 90Hochgurtel, M.; Biesinger, R.; Kroth, H.; Piecha, D.; Hofmann, M. W.; Krause, S.; Schaaf, O.; Nicolau, C.; Eliseev, A. V. Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological target. J. Med. Chem. 2003, 46, 356– 358, DOI: 10.1021/jm025589m[ACS Full Text], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD3s%252Fjtl2hsQ%253D%253D&md5=7f50c314bf5ee62b4c69c6c84fce6455Ketones as building blocks for dynamic combinatorial libraries: highly active neuraminidase inhibitors generated via selection pressure of the biological targetHochgurtel Matthias; Biesinger Ralf; Kroth Heiko; Piecha Dorothea; Hofmann Michael W; Krause Sonja; Schaaf Otmar; Nicolau Claude; Eliseev Alexey VJournal of medicinal chemistry (2003), 46 (3), 356-8 ISSN:0022-2623.New and potent inhibitors of neuraminidase, a key enzyme in the influenza virus activity, have been discovered in dynamic combinatorial libraries based on ketones and amines as building blocks. Selective synthesis of a number of inhibitors among multiple theoretically possible combinations of building blocks is driven by the presence of the target enzyme.
- 91Nasr, G.; Petit, E.; Vullo, D.; Winum, J. Y.; Supuran, C. T.; Barboiu, M. Carbonic anhydrase-encoded dynamic constitutional libraries: toward the discovery of isozyme-specific inhibitors. J. Med. Chem. 2009, 52, 4853– 4859, DOI: 10.1021/jm900449v[ACS Full Text], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXotF2ruro%253D&md5=1f928d3994682815692e117881d6e6d0Carbonic Anhydrase-Encoded Dynamic Constitutional Libraries: Toward the Discovery of Isozyme-Specific InhibitorsNasr, Gihane; Petit, Eddy; Vullo, Daniela; Winum, Jean-Yves; Supuran, Claudiu T.; Barboiu, MihailJournal of Medicinal Chemistry (2009), 52 (15), 4853-4859CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A constitutional dynamic library (CDL) was generated under thermodn. control by using the amino-carbonyl/imine interconversion as reversible chem., combined with noncovalent bonding within the active site of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Considering the pharmacol. importance to find isoform-selective CA inhibitors (CAIs), two of the 15 human (h) isoform, i.e., hCAI and hCA II, have been subjected to a parallel screening of the same CDL. The use of parallel constitutional screening of CDL chem. for the discovery of enzyme inhibitors is straightforward and it might provide initial insights toward the generation of efficient classes of selective, high affinity inhibitors. We demonstrate here that the high selectivity and specificity of inhibiting the hCA I and hCA II isoenzymes with some of the detected hits may be used to describe a complex constitutional behavior through component selection from the dynamic library, driven by the selective binding to the specific isoform active site. These results also point to the possibility of modulating the drug discovery methods by constitutional recomposition induced by a specific enzymic target.
- 92Bunyapaiboonsri, T.; Ramstrom, H.; Ramstrom, O.; Haiech, J.; Lehn, J. M. Generation of bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library. J. Med. Chem. 2003, 46, 5803– 5811, DOI: 10.1021/jm030917j[ACS Full Text], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXpt1WqsbY%253D&md5=5bcf324bf322ee8b06ae430ffd6e725dGeneration of Bis-Cationic Heterocyclic Inhibitors of Bacillus subtilis HPr Kinase/Phosphatase from a Ditopic Dynamic Combinatorial LibraryBunyapaiboonsri, Taridaporn; Ramstroem, Helena; Ramstroem, Olof; Haiech, Jacques; Lehn, Jean-MarieJournal of Medicinal Chemistry (2003), 46 (26), 5803-5811CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ditopic dynamic combinatorial libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries contg. up to 440 different constituents. Of all possible acyl hydrazones formed, active compds. contg. two terminal cationic heterocyclic recognition groups sepd. by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-aminobenzimidazole, was identified from the process.
- 93Bhardwaj, A.; Kaur, J.; Wuest, M.; Wuest, F. In situ click chemistry generation of cyclooxygenase-2 inhibitors. Nat. Commun. 2017, 8, 1, DOI: 10.1038/s41467-016-0009-6[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFWqt7fI&md5=32dc534437e3254fc9ce5f4839122d01In situ click chemistry generation of cyclooxygenase-2 inhibitorsBhardwaj, Atul; Kaur, Jatinder; Wuest, Melinda; Wuest, FrankNature Communications (2017), 8 (1), 1-14CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Cyclooxygenase-2 isoenzyme is a promising anti-inflammatory drug target, and overexpression of this enzyme is also assocd. with several cancers and neurodegenerative diseases. The amino-acid sequence and structural similarity between inducible cyclooxygenase-2 and housekeeping cyclooxygenase-1 isoforms present a significant challenge to design selective cyclooxygenase-2 inhibitors. Herein, we describe the use of the cyclooxygenase-2 active site as a reaction vessel for the in situ generation of its own highly specific inhibitors. Multi-component competitive-binding studies confirmed that the cyclooxygenase-2 isoenzyme can judiciously select most appropriate chem. building blocks from a pool of chems. to build its own highly potent inhibitor. Herein, with the use of kinetic target-guided synthesis, also termed as in situ click chem., we describe the discovery of two highly potent and selective cyclooxygenase-2 isoenzyme inhibitors. The in vivo anti-inflammatory activity of these two novel small mols. is significantly higher than that of widely used selective cyclooxygenase-2 inhibitors.
- 94Wang, Y.; Zhu, J.; Zhang, L. Discovery of cell-permeable O-GlcNAc transferase inhibitors via tethering in situ click chemistry. J. Med. Chem. 2017, 60, 263– 272, DOI: 10.1021/acs.jmedchem.6b01237[ACS Full Text], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFKksrnP&md5=eb17ed1f482911fef80c9f1fb80983daDiscovery of Cell-Permeable O-GlcNAc Transferase Inhibitors via Tethering in Situ Click ChemistryWang, Yue; Zhu, Jingjing; Zhang, LianwenJournal of Medicinal Chemistry (2017), 60 (1), 263-272CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)O-GlcNAc transferase (OGT) is a key enzyme involved in dynamic O-GlcNAcylation of nuclear and cytoplasmic proteins similar to phosphorylation. Discovery of cell-permeable OGT inhibitors is significant to clarify the function and regulatory mechanism of O-GlcNAcylation. This will establish the foundation for the development of therapeutic drugs for relevant diseases. Here, the authors report two cell-permeable OGT inhibitors (APNT and APBT), developed from low-activity precursors (IC50 > 1 mM) via "tethering in situ click chem. (TISCC)". Both of them were able to inhibit O-GlcNAcylation in cells without significant effects on cell viability. Unusual noncompetitive inhibition of OGT was helpful to discover novel inhibitors and explore the regulatory mechanism of OGT. The development of these mols. validates that TISCC can be utilized to discover novel lead compds. from components which exhibited very weak binding to the target.
- 95Namelikonda, N. K.; Manetsch, R. Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesis. Chem. Commun. (Cambridge, U. K.) 2012, 48, 1526– 1528, DOI: 10.1039/C1CC14724B[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtF2hsg%253D%253D&md5=70d29deebe58911e0f98e272c2650730Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesisNamelikonda, Niranjan Kumar; Manetsch, RomanChemical Communications (Cambridge, United Kingdom) (2012), 48 (10), 1526-1528CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)A practical, one-pot variant of the sulfo-click reaction was described, in which 9-fluorenylmethyl-protected thioesters are rapidly deprotected and reacted further with sulfonylazides to give N-acyl sulfonamides, e.g. I.
- 96Kulkarni, S. S.; Hu, X.; Doi, K.; Wang, H. G.; Manetsch, R. Screening of protein-protein interaction modulators via sulfo-click kinetic target-guided synthesis. ACS Chem. Biol. 2011, 6, 724– 732, DOI: 10.1021/cb200085q[ACS Full Text], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsFyqt7Y%253D&md5=c57b60a88631ce37bd5dbeaa3b2e2f35Screening of Protein-Protein Interaction Modulators via Sulfo-Click Kinetic Target-Guided SynthesisKulkarni, Sameer S.; Hu, Xiangdong; Doi, Kenichiro; Wang, Hong-Gang; Manetsch, RomanACS Chemical Biology (2011), 6 (7), 724-732CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Kinetic target-guided synthesis (TGS) and in situ click chem. are among unconventional discovery strategies having the potential to streamline the development of protein-protein interaction modulators (PPIMs). In kinetic TGS and in situ click chem., the target is directly involved in the assembly of its own potent, bidentate ligand from a pool of reactive fragments. Herein, we report the use and validation of kinetic TGS based on the sulfo-click reaction between thio acids and sulfonyl azides as a screening and synthesis platform for the identification of high-quality PPIMs. Starting from a randomly designed library consisting of 9 thio acids and 9 sulfonyl azides leading to 81 potential acylsulfonamides, the target protein, Bcl-XL, selectively assembled four PPIMs, acylsulfonamides SZ4TA2, SZ7TA2, SZ9TA1, and SZ9TA5, which have been shown to modulate Bcl-XL/BH3 interactions. To further investigate the Bcl-XL templation effect, control expts. were carried out using two mutants of Bcl-XL. In one mutant, phenylalanine Phe131 and aspartic acid Asp133, which are crit. for the BH3 domain binding, were substituted by alanines, while arginine Arg139, a residue identified to play a crucial role in the binding of ABT-737, a BH3 mimetic, was replaced by an alanine in the other mutant. Incubation of these mutants with the reactive fragments and subsequent LC/MS-SIM anal. confirmed that these building block combinations yield the corresponding acylsulfonamides at the BH3 binding site, the actual "hot spot" of Bcl-XL. These results validate kinetic TGS using the sulfo-click reaction as a valuable tool for the straightforward identification of high-quality PPIMs.
- 97Antti, H.; Sellstedt, M. Cell-based kinetic target-guided synthesis of an enzyme Inhibitor. ACS Med. Chem. Lett. 2018, 9, 351– 353, DOI: 10.1021/acsmedchemlett.7b00535[ACS Full Text], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjvFansr8%253D&md5=117e4a2748228d419128f2d2046c2e35Cell-Based Kinetic Target-Guided Synthesis of an Enzyme InhibitorAntti, Henrik; Sellstedt, MagnusACS Medicinal Chemistry Letters (2018), 9 (4), 351-353CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Finding a new drug candidate for a selected target is an expensive and time-consuming process. Target guided-synthesis, or in situ click chem., is a concept where the drug target is used to template the formation of its own inhibitors from reactive building blocks. This could simplify the identification of drug candidates. However, with the exception of one example of an RNA-target, target-guided synthesis has always employed purified targets. This limits the no. of targets that can be screened by the method. By applying methods from the field of metabolomics, we demonstrate that target-guided synthesis with protein targets also can be performed directly in cell-based systems. These methods offer new possibilities to conduct screening for drug candidates of difficult protein targets in cellular environments.
- 98Lebraud, H.; Wright, D. J.; Johnson, C. N.; Heightman, T. D. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras. ACS Cent. Sci. 2016, 2, 927– 934, DOI: 10.1021/acscentsci.6b00280[ACS Full Text], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFOltbbJ&md5=4cc9b4aaba6ee03cd2d4ea97a72728a5Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting ChimerasLebraud, Honorine; Wright, David J.; Johnson, Christopher N.; Heightman, Tom D.ACS Central Science (2016), 2 (12), 927-934CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)Selective degrdn. of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC mols. incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional mols. require significant linker optimization and possess high mol. wt., which can limit cellular permeation, soly., and other drug-like properties. We show here that the hetero-bifunctional mol. can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide deriv. which reacts rapidly with a trans-cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC mol. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncol. targets, BRD4 and ERK1/2. ERK1/2 degrdn. was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degrdn.
- 99(a) Sindelar, M.; Wanner, K. T. Library screening by means of mass spectrometry (MS) binding assays-exemplarily demonstrated for a pseudostatic library addressing γ-aminobutyric acid (GABA) transporter 1 (GAT1). ChemMedChem 2012, 7, 1678– 1690, DOI: 10.1002/cmdc.201200201[Crossref], [PubMed], [CAS], Google Scholar.99ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot1Khu7c%253D&md5=98216d9b84dca9be3dd0b34fe4602461Library Screening by Means of Mass Spectrometry (MS) Binding Assays-Exemplarily Demonstrated for a Pseudostatic Library Addressing γ-Aminobutyric Acid (GABA) Transporter 1 (GAT1)Sindelar, Miriam; Wanner, Klaus T.ChemMedChem (2012), 7 (9), 1678-1690, S1678/1-S1678/7CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)In the present study, the application of mass spectrometry (MS) binding assays as a tool for library screening is reported. For library generation, dynamic combinatorial chem. (DCC) was used. These libraries can be screened by MS binding assays when appropriate measures are taken to render the libraries pseudostatic. That way, the efficiency of MS binding assays to det. ligand binding in compd. screening with the ease of library generation by DCC is combined. The feasibility of this approach is shown for γ-aminobutyric acid (GABA) transporter 1 (GAT1) as a target, representing the most important subtype of the GABA transporters. For the screening, hydrazone libraries were employed that were generated in the presence of the target by reacting various sets of aldehydes with a hydrazine deriv. that is delineated from piperidine-3-carboxylic acid (nipecotic acid), a common fragment of known GAT1 inhibitors. To ensure that the library generated is pseudostatic, a large excess of the nipecotic acid deriv. is employed. As the library is generated in a buffer system suitable for binding and the target is already present, the mixts. can be directly analyzed by MS binding assays-the process of library generation and screening thus becoming simple to perform. The binding affinities of the hits identified by deconvolution were confirmed in conventional competitive MS binding assays performed with single compds. obtained by sep. synthesis. In this way, two nipecotic acid derivs. exhibiting a biaryl moiety, 1-{2-[2'-(1,1'-biphenyl-2-ylmethylidene)hydrazine]ethyl}piperidine-3-carboxylic acid and 1-(2-{2'-[1-(2-thiophenylphenyl)methylidene]hydrazine}ethyl)piperidine-3-carboxylic acid, were potent GAT1 ligands exhibiting pKi values of 6.186±0.028 and 6.229±0.039, resp. This method enables screening of libraries, whether generated by conventional chem. or DCC, and is applicable to all kinds of targets including membrane-bound targets such as G protein coupled receptors (GPCRs), ion channels and transporters. As such, this strategy displays high potential in the drug discovery process.(b) Sindelar, M.; Lutz, T. A.; Petrera, M.; Wanner, K. T. Focused pseudostatic hydrazone libraries screened by mass spectrometry binding assay: optimizing affinities toward γ-aminobutyric acid transporter 1. J. Med. Chem. 2013, 56, 1323– 1340, DOI: 10.1021/jm301800j[ACS Full Text.], [CAS], Google Scholar99bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCns7g%253D&md5=747ff650d39eaa3a01dedfdac7058191Focused Pseudostatic Hydrazone Libraries Screened by Mass Spectrometry Binding Assay: Optimizing Affinities toward γ-Aminobutyric Acid Transporter 1Sindelar, Miriam; Lutz, Toni A.; Petrera, Marilena; Wanner, Klaus T.Journal of Medicinal Chemistry (2013), 56 (3), 1323-1340CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mass spectrometric (MS) binding assays, a powerful tool to det. affinities of single drug candidates toward chosen targets, were recently demonstrated to be suitable for the screening of compd. libraries generated with reactions of dynamic combinatorial chem. when rendering libraries pseudostatic. Screening of small hydrazone libraries targeting γ-aminobutyric acid transporter 1 (GAT1), the most abundant γ-aminobutyric acid (GABA) transporter in the central nervous system, revealed two nipecotic acid derived binders with submicromolar affinities. Starting from the biphenyl carrying hit as lead structure, the objective of the present study was to discover novel high affinity GAT1 binders by screening of biphenyl focused pseudo-static hydrazone libraries formed from hydrazine (I) and 36 biphenylcarbaldehydes. Hydrazone (II) that carried a 2',4'-dichlorobiphenyl residue was found to be the most potent binder with low nanomolar affinity (pKi = 8.094±0.098). When stable carba analogs of representative hydrazones were synthesized and evaluated, the best binder 13z was again displaying the 2',4'-dichlorobiphenyl moiety (pKi = 6.930±0.021).(c) Hauke, T. J.; Wein, T.; Höfner, G.; Wanner, K. T. Novel allosteric ligands of γ-aminobutyric acid transporter 1 (GAT1) by MS based screening of pseudostatic hydrazone libraries. J. Med. Chem. 2018, 61, 10310– 10332, DOI: 10.1021/acs.jmedchem.8b01602[ACS Full Text.], [CAS], Google Scholar99chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVCisLbJ&md5=c7cad956702acfe6d59dea0c2faa14cdNovel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone LibrariesHauke, Tobias J.; Wein, Thomas; Hoefner, Georg; Wanner, Klaus T.Journal of Medicinal Chemistry (2018), 61 (22), 10310-10332CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5- instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compds. and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured compd. I bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake expts. revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid deriv. up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivs. could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.(d) Huber, S. K.; Höfner, G.; Wanner, K. T. Identification of pyrrolidine-3-acetic acid derived oximes as potent inhibitors of γ-aminobutyric acid transporter 1 through library screening with MS binding assays. ChemMedChem 2018, 13, 2488– 2503, DOI: 10.1002/cmdc.201800556[Crossref], [PubMed], [CAS], Google Scholar99dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlentr%252FE&md5=ca9cb3a556ebe7a2b699ce3fc86a4bf8Identification of Pyrrolidine-3-acetic Acid Derived Oximes as Potent Inhibitors of γ-Aminobutyric Acid Transporter 1 through Library Screening with MS Binding AssaysHuber, Simone K.; Hoefner, Georg; Wanner, Klaus T.ChemMedChem (2018), 13 (23), 2488-2503CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)In this study, pyrrolidine-3-acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ-aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine-3-acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution expts. to identify single oximes responsible for the obsd. activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine-3-acetic acid motif were found, of which the most potent oxime, possessing a 2',4'-dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi=7.87±0.01).
- 100(a) Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; Yeoh, K. K.; Tian, Y.-M.; Claridge, T. D. W.; Rgatcliffe, P. J.; Woon, E. C. Y.; Schofield, C. J. Dynamic combinatorial chemistry employing boronic acids/boronate esters leads to potent oxygenase inhibitors. Angew. Chem., Int. Ed. 2012, 51, 6672– 6675, DOI: 10.1002/anie.201202000[Crossref], [CAS], Google Scholar.100ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xns1WjtL0%253D&md5=1e6b2d573dec343072822882f9cccaefDynamic Combinatorial Chemistry Employing Boronic Acids/Boronate Esters Leads to Potent Oxygenase InhibitorsDemetriades, Marina; Leung, Ivanhoe K. H.; Chowdhury, Rasheduzzaman; Chan, Mun Chiang; McDonough, Michael A.; Yeoh, Kar Kheng; Tian, Ya-Min; Claridge, Timothy D. W.; Ratcliffe, Peter J.; Woon, Esther C. Y.; Schofield, Christopher J.Angewandte Chemie, International Edition (2012), 51 (27), 6672-6675, S6672/1-S6672/53CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The reversible reaction of boronic acids with alcs. to form boronate esters, coupled to protein mass spectrometry analyses, was used to discover potent oxygenase inhibitors. This dynamic combinatorial mass spectrometry technique could potentially be applied to the identification of other protein inhibitors.(b) Woon, E. C. Y.; Demetriades, M.; Bagg, E. A. L.; Aik, W. S.; Krylova, S. M.; Ma, J. H. Y.; Chan, M. C.; Walport, L. J.; Wegman, D. W.; Dack, K. N.; McDonough, M. A.; Krylov, S. N.; Schofield, C. J. Dynamic combinatorial mass spectrometry leads to inhibitors of a 2-oxoglutarate dependent nucleic acid demethylase. J. Med. Chem. 2012, 55, 2173– 2184, DOI: 10.1021/jm201417e[ACS Full Text.], [CAS], Google Scholar100bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtVymur0%253D&md5=a7e7f3fae71f6764ce34ac1d5737cffcDynamic Combinatorial Mass Spectrometry Leads to Inhibitors of a 2-Oxoglutarate-Dependent Nucleic Acid DemethylaseWoon, Esther C. Y.; Demetriades, Marina; Bagg, Eleanor A. L.; Aik, WeiShen; Krylova, Svetlana M.; Ma, Jerome H. Y.; Chan, MunChiang; Walport, Louise J.; Wegman, David W.; Dack, Kevin N.; McDonough, Michael A.; Krylov, Sergey N.; Schofield, Christopher J.Journal of Medicinal Chemistry (2012), 55 (5), 2173-2184CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)2-Oxoglutarate-dependent nucleic acid demethylases are of biol. interest because of their roles in nucleic acid repair and modification. Although some of these enzymes are linked to physiol., their regulatory roles are unclear. Hence, there is a desire to develop selective inhibitors for them; we report studies on AlkB, which reveal it as being amenable to selective inhibition by small mols. Dynamic combinatorial chem. linked to mass spectrometric analyses (DCMS) led to the identification of lead compds., one of which was analyzed by crystallog. Subsequent structure-guided studies led to the identification of inhibitors of improved potency, some of which were shown to be selective over two other 2OG oxygenases. The work further validates the use of the DCMS method and will help to enable the development of inhibitors of nucleic acid modifying 2OG oxygenases both for use as functional probes and, in the longer term, for potential therapeutic use.(c) Rose, N. R.; Woon, E. C. Y.; Kingham, G. L.; King, O. N. F.; Mecinovic, J.; Clifton, I. J.; Ng, S. S.; Talib-Hardy, J.; Oppermann, U.; McDonough, M. A.; Schofield, C. J. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. J. Med. Chem. 2010, 53, 1810– 1818, DOI: 10.1021/jm901680b[ACS Full Text], [CAS], Google Scholar100chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXnvFWnsQ%253D%253D&md5=3eb3c36d91f46193946f64288ea9ccaeSelective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic ApproachesRose, Nathan R.; Woon, Esther C. Y.; Kingham, Guy L.; King, Oliver N. F.; Mecinovic, Jasmin; Clifton, Ian J.; Ng, Stanley S.; Talib-Hardy, Jobina; Oppermann, Udo; McDonough, Michael A.; Schofield, Christopher J.Journal of Medicinal Chemistry (2010), 53 (4), 1810-1818CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of Nε-methylated lysine residues in histones. Here, studies on the inhibition of the JMJD2 subfamily of histone demethylases are reported, employing binding analyses by non-denaturing mass spectrometry (MS), dynamic combinatorial chem. coupled to MS, turnover assays, and crystallog. The results of initial binding and inhibition assays directed the prodn. and anal. of a set of N-oxalyl-D-tyrosine derivs. to explore the extent of a sub-pocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compds.
- 101Das, M.; Tianming, Y.; Jinghua, D.; Prasetya, F.; Yiming, X.; Wong, K.; Cheong, A.; Woon, E. C. Y. Multi-protein dynamic combinatorial chemistry: a novel strategy that leads to simultaneous discovery of subfamily-selective inhibitors for nucleic acid demethylases FTO and ALKBH3. Chem. Asian J. 2018, 13, 2854, DOI: 10.1002/asia.201800729[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslaiu7%252FK&md5=2e8dca74858c93f2cbf8f77b9cb5660dMultiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3Das, Mohua; Yang, Tianming; Dong, Jinghua; Prasetya, Fransisca; Xie, Yiming; Wong, Kendra H. Q.; Cheong, Adeline; Woon, Esther C. Y.Chemistry - An Asian Journal (2018), 13 (19), 2854-2867CODEN: CAAJBI; ISSN:1861-4728. (Wiley-VCH Verlag GmbH & Co. KGaA)Dynamic combinatorial chem. (DCC) is a powerful supramol. approach for discovering ligands for biomols. To date, most, if not all, biol. templated DCC systems employ only a single biomol. to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic "thermal tag" with the sensitivity of differential scanning fluorimetry (DSF). This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clin. important epigenetic enzymes: FTO (7; IC50 = 2.6 μm) and ALKBH3 (8; IC50 = 3.7 μm). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.
- 102Jana, S.; Panda, D.; Saha, P.; Pantos, D.; Dash, J. Dynamic generation of G-quadruplex DNA ligands by target-guided combinatorial chemistry on a magnetic nano-platform. J. Med. Chem. 2019, 62, 762, DOI: 10.1021/acs.jmedchem.8b01459[ACS Full Text], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKrsLvK&md5=af30b67c78bee38c1bcc5b71341bdd31Dynamic Generation of G-Quadruplex DNA Ligands by Target-Guided Combinatorial Chemistry on a Magnetic NanoplatformJana, Snehasish; Panda, Deepanjan; Saha, Puja; Pantos, G. Dan; Dash, JyotirmayeeJournal of Medicinal Chemistry (2019), 62 (2), 762-773CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Dynamic combinatorial chem. (DCC) has emerged as a promising strategy for template-driven selection of high-affinity ligands for biol. targets from equilibrating combinatorial libraries. However, only a few examples using disulfide-exchange-based DCC are reported for nucleic acid targets. Herein, gold-coated magnetic nanoparticle-conjugated DNA targets can be used as templates for dynamic selection of ligands from an imine-based combinatorial library. The implementation of DCC using DNA nanotemplates enables efficient identification of the lead compds., from the dynamic combinatorial library via magnetic decantation. It further allows quick sepn. of DNA nanotemplates for reuse in DCC reactions. The identified lead compd. exhibits significant quadruplex vs. duplex DNA selectivity and suppresses promoter activity of c-MYC gene that contains G-quadruplex DNA forming sequence in the upstream promoter region. Further cellular expts. indicated that the lead compd. is able to permeate into cell nuclei and trigger a DNA damage response in cancer cells.
- 103Tu, J.; Xu, M.; Franzini, R. Dissociative bioorthogonal reactions. ChemBioChem 2019, DOI: 10.1002/cbic.201800810
- 104Li, J.; Chen, P. R. Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat. Chem. Biol. 2016, 12, 129– 137, DOI: 10.1038/nchembio.2024[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVCis74%253D&md5=6b563f0c618e43f97bf4cea26c060451Development and application of bond cleavage reactions in bioorthogonal chemistryLi, Jie; Chen, Peng R.Nature Chemical Biology (2016), 12 (3), 129-137CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)A review. Bioorthogonal chem. reactions are a thriving area of chem. research in recent years as an unprecedented technique to dissect native biol. processes through chem.-enabled strategies. However, current concepts of bioorthogonal chem. have largely centered on bond formation reactions between two mutually reactive bioorthogonal handles. Recently, in a reverse strategy, a collection of bond cleavage reactions has emerged with excellent biocompatibility. These reactions have expanded the bioorthogonal chem. repertoire, enabling an array of exciting new biol. applications that range from the chem. controlled spatial and temporal activation of intracellular proteins and small-mol. drugs to the direct manipulation of intact cells under physiol. conditions. Here the authors highlight the development and applications of these bioorthogonal cleavage reactions. Furthermore, the authors lay out challenges and propose future directions along this appealing avenue of research.
- 105(a) Unciti-Broceta, A.; Johansson, E. M.; Yusop, R. M.; Sanchez-Martin, R. M.; Bradley, M. Synthesis of polystyrene microspheres and functionalization with Pd(0) nanoparticles to perform bioorthogonal organometallic chemistry in living cells. Nat. Protoc. 2012, 7, 1207– 1218, DOI: 10.1038/nprot.2012.052[Crossref], [PubMed], [CAS], Google Scholar.105ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XnslSmur8%253D&md5=7ab4fa74d57436f77bb70646bf15a794Synthesis of polystyrene microspheres and functionalization with Pd0 nanoparticles to perform bioorthogonal organometallic chemistry in living cellsUnciti-Broceta, Asier; Johansson, Emma M. V.; Yusop, Rahimi M.; Sanchez-Martin, Rosario M.; Bradley, MarkNature Protocols (2012), 7 (6), 1207-1218CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)We have developed miniaturized heterogeneous Pd0-catalysts (Pd0-microspheres) with the ability to enter cells, stay harmlessly within the cytosol and mediate efficient bioorthogonal organometallic chemistries (e.g., allylcarbamate cleavage and Suzuki-Miyaura cross-coupling). This approach is a major addn. to the toolbox available for performing chem. reactions within cells. Here we describe a full protocol for the synthesis of the Pd0-microspheres from readily available starting materials (by the synthesis of size-controlled amino-functionalized polystyrene microspheres), as well as for their characterization (electron microscopy and palladium quantitation) and functional validation ('in soln.' and 'in cytoplasm' conversions). From the beginning of the synthesis to functional evaluation of the catalytic device requires 5 d of work.(b) Yusop, R. M.; Unciti-Broceta, A.; Johansson, E. M.; Sanchez-Martin, R. M.; Bradley, M. Palladium-mediated intracellular chemistry. Nat. Chem. 2011, 3, 239– 243, DOI: 10.1038/nchem.981[Crossref], [PubMed], [CAS], Google Scholar.105bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXit1Wru7s%253D&md5=f6011d340f1d5666475190a2a66b3313Palladium-mediated intracellular chemistryYusop, Rahimi M.; Unciti-Broceta, Asier; Johansson, Emma M. V.; Sanchez-Martin, Rosario M.; Bradley, MarkNature Chemistry (2011), 3 (3), 239-243CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Many important intracellular biochem. reactions are modulated by transition metals, typically in the form of metalloproteins. The ability to carry out selective transformations inside a cell would allow researchers to manipulate or interrogate innumerable biol. processes. Here, we show that palladium nanoparticles trapped within polystyrene microspheres can enter cells and mediate a variety of Pd0-catalyzed reactions, such as allylcarbamate cleavage and Suzuki-Miyaura cross-coupling. The work provides the basis for the customization of heterogeneous unnatural catalysts as tools to carry out artificial chemistries within cells. Such in cellular synthesis has potential for a plethora of applications ranging from cellular labeling to synthesis of modulators or inhibitors of cell function.(c) Unciti-Broceta, A. Bioorthogonal catalysis: Rise of the nanobots. Nat. Chem. 2015, 7, 538– 539, DOI: 10.1038/nchem.2291[Crossref], [PubMed], [CAS], Google Scholar.105chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht1yjs7%252FK&md5=2feca0ef4c0b075240520c65f83540f8Bioorthogonal catalysis Rise of the nanobotsUnciti-Broceta, AsierNature Chemistry (2015), 7 (7), 538-539CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)Bioorthogonal catalysis provides new ways of mediating artificial transformations in living environs. Now, researchers have developed a nanodevice whose catalytic activity can be regulated by host-guest chem.(d) Weiss, J. T.; Dawson, J. C.; Fraser, C.; Rybski, W.; Torres-Sanchez, C.; Bradley, M.; Patton, E. E.; Carragher, N. O.; Unciti-Broceta, A. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine. J. Med. Chem. 2014, 57, 5395– 5404, DOI: 10.1021/jm500531z[ACS Full Text.], [CAS], Google Scholar105dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXos1ajs7c%253D&md5=2d354f262acebde27b4d1345fe0175b6Development and Bio-Orthogonal Activation of Palladium-Labile Prodrugs of GemcitabineWeiss, Jason T.; Dawson, John C.; Fraser, Craig; Rybski, Witold; Torres-Sanchez, Carmen; Bradley, Mark; Patton, E. Elizabeth; Carragher, Neil O.; Unciti-Broceta, AsierJournal of Medicinal Chemistry (2014), 57 (12), 5395-5404CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bio-orthogonal chem. has become one of the main driving forces in current chem. biol., inspiring the search for novel bio-compatible chemo-specific reactions for the past decade. Alongside the well-established labeling strategies that originated the bio-orthogonal paradigm, we have recently proposed the use of heterogeneous palladium chem. and bio-orthogonal Pd0-labile prodrugs to develop spatially targeted therapies. Herein, we report the generation of biol. inert precursors of cytotoxic gemcitabine by introducing Pd0-cleavable groups in positions that are mechanistically relevant for gemcitabine's pharmacol. activity. Cell viability studies in pancreatic cancer cells showed that carbamate functionalization of the 4-amino group of gemcitabine significantly reduced ( > 23-fold) the prodrugs' cytotoxicity. The N-propargyloxycarbonyl (N-Poc) moiety displayed the highest sensitivity to heterogeneous palladium catalysis under bio-compatible conditions, with a reaction half-life of less than 6 h. Zebrafish studies with allyl, propargyl, and benzyl carbamate-protected rhodamines confirmed N-Poc as the most suitable masking group for implementing in vivo bio-orthogonal organo-metallic chem.(e) Weiss, J. T.; Dawson, J. C.; Macleod, K. G.; Rybski, W.; Fraser, C.; Torres-Sanchez, C.; Patton, E. E.; Bradley, M.; Carragher, N. O.; Unciti-Broceta, A. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Commun. 2014, 5, 3277, DOI: 10.1038/ncomms4277[Crossref], [PubMed], [CAS], Google Scholar.105ehttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cvkslGhtw%253D%253D&md5=0eea3d70b9d493cad2223e5d3ca87514Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approachWeiss Jason T; Dawson John C; Macleod Kenneth G; Fraser Craig; Carragher Neil O; Unciti-Broceta Asier; Rybski Witold; Patton E Elizabeth; Torres-Sanchez Carmen; Bradley MarkNature communications (2014), 5 (), 3277 ISSN:.A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.(f) Weiss, J. T.; Fraser, C.; Rubio-Ruiz, B.; Myers, S. H.; Crispin, R.; Dawson, J. C.; Brunton, V. G.; Patton, E. E.; Carragher, N. O.; Unciti-Broceta, A. N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell culture. Front Chem. 2014, 2, 56, DOI: 10.3389/fchem.2014.00056[Crossref], [PubMed], [CAS], Google Scholar.105fhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2M%252Fhs1Gktw%253D%253D&md5=767f9b4f959fef7c4a558cb373571de6N-alkynyl derivatives of 5-fluorouracil: susceptibility to palladium-mediated dealkylation and toxigenicity in cancer cell cultureWeiss Jason T; Fraser Craig; Rubio-Ruiz Belen; Myers Samuel H; Dawson John C; Brunton Valerie G; Carragher Neil O; Unciti-Broceta Asier; Crispin Richard; Patton E ElizabethFrontiers in chemistry (2014), 2 (), 56 ISSN:2296-2646.Palladium-activated prodrug therapy is an experimental therapeutic approach that relies on the unique chemical properties and biocompatibility of heterogeneous palladium catalysis to enable the spatially-controlled in vivo conversion of a biochemically-stable prodrug into its active form. This strategy, which would allow inducing local activation of systemically administered drug precursors by mediation of an implantable activating device made of Pd(0), has been proposed by our group as a way to reach therapeutic levels of the active drug in the affected tissue/organ while reducing its systemic toxicity. In the seminal study of such an approach, we reported that propargylation of the N1 position of 5-fluorouracil suppressed the drug's cytotoxic properties, showed high stability in cell culture and facilitated the bioorthogonal restoration of the drug's pharmacological activity in the presence of extracellular Pd(0)-functionalized resins. To provide additional insight on the properties of this system, we have investigated different N1-alkynyl derivatives of 5-fluorouracil and shown that the presence of substituents near the triple bond influence negatively on its sensitivity to palladium catalysis under biocompatible conditions. Comparative studies of the N1- vs. the N3-propargyl derivatives of 5-fluorouracil revealed that masking each or both positions equally led to inactive derivatives (>200-fold reduction of cytotoxicity relative to the unmodified drug), whereas the depropargylation process occurred faster at the N1 position than at the N3, thus resulting in greater toxigenic properties in cancer cell culture.(g) Weiss, J. T.; Carragher, N. O.; Unciti-Broceta, A. Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy. Sci. Rep. 2015, 5, 9329, DOI: 10.1038/srep09329[Crossref], [PubMed], [CAS], Google Scholar.105ghttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFKku7rM&md5=f962ebb91e375e44756ae19e6596e275Palladium-Mediated Dealkylation of N-Propargyl-Floxuridine as a Bioorthogonal Oxygen-Independent Prodrug StrategyWeiss, Jason T.; Carragher, Neil O.; Unciti-Broceta, AsierScientific Reports (2015), 5 (), 9329CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Herein we report the development and biol. screening of a bioorthogonal palladium-labile prodrug of the nucleoside analog floxuridine, a potent antineoplastic drug used in the clinic to treat advanced cancers. N-propargylation of the N3 position of its uracil ring resulted in a vast redn. of its biol. activity (∼6,250-fold). Cytotoxic properties were bioorthogonally rescued in cancer cell culture by heterogeneous palladium chem. both in normoxia and hypoxia. Within the same environment, the reported chemo-reversible prodrug exhibited up to 1,450-fold difference of cytotoxicity whether it was in the absence or presence of the extracellular palladium source, underlining the precise modulation of bioactivity enabled by this bioorthogonally-activated prodrug strategy.(h) Rubio-Ruiz, B.; Weiss, J. T.; Unciti-Broceta, A. Efficient palladium-triggered release of vorinostat from a bioorthogonal precursor. J. Med. Chem. 2016, 59, 9974– 9980, DOI: 10.1021/acs.jmedchem.6b01426[ACS Full Text], [CAS], Google Scholar105hhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslGht7fL&md5=0549af63fb54dd8135a81b374939f59dEfficient Palladium-Triggered Release of Vorinostat from a Bioorthogonal PrecursorRubio-Ruiz, Belen; Weiss, Jason T.; Unciti-Broceta, AsierJournal of Medicinal Chemistry (2016), 59 (21), 9974-9980CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Bioorthogonal uncaging strategies have recently emerged as an exptl. therapeutic approach to control drug release. Herein we report a novel masking strategy that enables to modulate the metal chelating properties of hydroxamic acid groups by bioorthogonal chem. using Pd-functionalized resins. This novel approach allowed to devise an inactive precursor of the histone deacetylase inhibitor vorinostat that was efficiently uncaged by heterogeneous Pd catalysis in cell culture models of glioma and lung cancer.
- 106Lv, T.; Wu, J.; Kang, F.; Wang, T.; Wan, B.; Lu, J. J.; Zhang, Y.; Huang, Z. Synthesis and evaluation of O(2)-derived diazeniumdiolates activatable via bioorthogonal chemistry reactions in living cells. Org. Lett. 2018, 20, 2164– 2167, DOI: 10.1021/acs.orglett.8b00423[ACS Full Text], [CAS], Google Scholar106https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmt1Cns74%253D&md5=135a8b5f46dc617e211b6d32b93c462cSynthesis and Evaluation of O2-Derived Diazeniumdiolates Activatable via Bioorthogonal Chemistry Reactions in Living CellsLv, Tian; Wu, Jianbing; Kang, Fenghua; Wang, Tingting; Wan, Boheng; Lu, Jin-Jian; Zhang, Yihua; Huang, ZhangjianOrganic Letters (2018), 20 (8), 2164-2167CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)A class of O2-alkyl derived diazeniumdiolates R1R2NN(O-):N+OCH2C≡CH (NR1R2 = pyrrolidino, 4-methylpiperazino, morpholino, diethylamino, 2-hydroxyethylamino), R1R2NN(O-):N+OCH2CH:CH2 (R1R2N = pyrrolidino) and I (R = CH2C≡CH, CH2CH:CH2, C:C:CH2) were designed and synthesized as new bioorthogonal NO precursors, which can be effectively uncaged in the presence of a palladium catalyst via bioorthogonal bond cleavage reactions to generate NO in living cancer cells, eliciting potent antiproliferative activity.
- 107Li, J.; Jia, S.; Chen, P. R. Diels-Alder reaction-triggered bioorthogonal protein decaging in living cells. Nat. Chem. Biol. 2014, 10, 1003– 1005, DOI: 10.1038/nchembio.1656[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVGiurfM&md5=4723cef7d02aec13267b61d08c9517a6Diels-Alder reaction-triggered bioorthogonal protein decaging in living cellsLi, Jie; Jia, Shang; Chen, Peng R.Nature Chemical Biology (2014), 10 (12), 1003-1005CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Small mols. that specifically activate an intracellular protein of interest are highly desirable. A generally applicable strategy, however, remains elusive. Herein we describe a small mol.-triggered bioorthogonal protein decaging technique that relies on the inverse electron-demand Diels-Alder reaction for eliminating a chem. caged protein side chain within living cells. This method permits the efficient activation of a given protein (for example, an enzyme) in its native cellular context within minutes.
- 108Perez-Lopez, A. M.; Rubio-Ruiz, B.; Sebastián, V.; Hamilton, L.; Adam, C.; Bray, T. L.; Irusta, S.; Brennan, P. M.; Lloyd-Jones, G. C.; Sieger, D.; Santamaría, J.; Unciti-Broceta, A. Gold-triggered uncaging chemistry in living systems. Angew. Chem., Int. Ed. 2017, 56, 12548– 12552, DOI: 10.1002/anie.201705609[Crossref], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlSmur%252FF&md5=34046f0a80e09abd4dc6e8f8b5f39584Gold-Triggered Uncaging Chemistry in Living SystemsPerez-Lopez, Ana M.; Rubio-Ruiz, Belen; Sebastian, Victor; Hamilton, Lloyd; Adam, Catherine; Bray, Thomas L.; Irusta, Silvia; Brennan, Paul M.; Lloyd-Jones, Guy C.; Sieger, Dirk; Santamaria, Jesus; Unciti-Broceta, AsierAngewandte Chemie, International Edition (2017), 56 (41), 12548-12552CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of mols. in complex biol. systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs.
- 109Devaraj, N. K. The future of bioorthogonal chemistry. ACS Cent. Sci. 2018, 4, 952– 959, DOI: 10.1021/acscentsci.8b00251[ACS Full Text], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlGhu7rN&md5=563756ff99c569baa5014a7843d1f0ecThe Future of Bioorthogonal ChemistryDevaraj, Neal K.ACS Central Science (2018), 4 (8), 952-959CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)A review. Bioorthogonal reactions have found widespread use in applications ranging from glycan engineering to in vivo imaging. Researchers have devised numerous reactions that can be predictably performed in a biol. setting. Depending on the requirements of the intended application, one or more reactions from the available toolkit can be readily deployed. As an increasing no. of investigators explore and apply chem. reactions in living systems, it is clear that there are a myriad of ways in which the field may advance. This article presents an outlook on the future of bioorthogonal chem. I discuss currently emerging opportunities and speculate on how bioorthogonal reactions might be applied in research and translational settings. I also outline hurdles that must be cleared if progress toward these goals is to be made. Given the incredible past successes of bioorthogonal chem. and the rapid pace of innovations in the field, the future is undoubtedly very bright.
- 110(a) Zheng, Y.; Ji, X.; Yu, B.; Ji, K.; Gallo, D.; Csizmadia, E.; Zhu, M.; Choudhury, M. R.; De La Cruz, L. K. C.; Chittavong, V.; Pan, Z.; Yuan, Z.; Otterbein, L. E.; Wang, B. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nat. Chem. 2018, 10, 787, DOI: 10.1038/s41557-018-0055-2[Crossref], [PubMed], [CAS], Google Scholar.110ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps1KktLk%253D&md5=148c528d5a8c3851abc31145a7b39253Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxideZheng, Yueqin; Ji, Xingyue; Yu, Bingchen; Ji, Kaili; Gallo, David; Csizmadia, Eva; Zhu, Mengyuan; Roy Choudhury, Manjusha; De La Cruz, Ladie Kimberly C.; Chittavong, Vayou; Pan, Zhixiang; Yuan, Zhengnan; Otterbein, Leo E.; Wang, BingheNature Chemistry (2018), 10 (7), 787-794CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Controlled activation is a crit. component in prodrug development. Here we report a concn.-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biol. and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of mols. and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the crit. feasibility of treating clin. relevant diseases such as acute liver injury and cancer.(b) Ji, X.; Pan, Z.; Yu, B.; De La Cruz, L. K.; Zheng, Y.; Ke, B.; Wang, B. Click and release: bioorthogonal approaches to ″on-demand″ activation of prodrugs. Chem. Soc. Rev. 2019, 48, 1077, DOI: 10.1039/C8CS00395E[Crossref], [PubMed], [CAS], Google Scholar110bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisFGjsbs%253D&md5=724cfdbebebc0e5625eb1bf62b04f594Click and release: bioorthogonal approaches to "on-demand" activation of prodrugsJi, Xingyue; Pan, Zhixiang; Yu, Bingchen; De La Cruz, Ladie Kimberly; Zheng, Yueqin; Ke, Bowen; Wang, BingheChemical Society Reviews (2019), 48 (4), 1077-1094CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Prodrug approaches represent an excellent soln. to certain pharmaceutical issues commonly encountered in the drug discovery and development process. Along this line, the chem. needed for the bio-reversible derivatization of drug functional groups for on-demand release is crit. In recent years, "click and release" approaches have shown great promise in the design of prodrugs because of their bioorthogonality and controlled bond-cleavage, which help ensure prodrug stability during circulation and ready cleavage at the desired site of action. This review highlights recent developments of this research field and discusses issues yet to be addressed.
- 111Klán, P.; Šolomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.; Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev. 2013, 113, 119– 191, DOI: 10.1021/cr300177k[ACS Full Text], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhvVyiurvL&md5=b8defe84c6c629e44d429f82fa4eb5f0Photoremovable Protecting Groups in Chemistry and Biology: Reaction Mechanisms and EfficacyKlan, Petr; Solomek, Tomas; Bochet, Christian G.; Blanc, Aurelien; Givens, Richard; Rubina, Marina; Popik, Vladimir; Kostikov, Alexey; Wirz, JakobChemical Reviews (Washington, DC, United States) (2013), 113 (1), 119-191CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Photoremovable (sometimes called photoreleasable, photocleavable or photoactivatable) protecting groups (PPGs) provide spatial and temporal control over the release of various chems. such as bioagents (neurotransmitters and cell-signaling mols.), acids, bases, Ca2+ ions, oxidants, insecticides, phermones, fragrances, etc. The present review covers recent developments in the field, focusing on the scope, limitations, and applications of PPGs, which are used to release org. mols. Simplified basic structures of PPGs discussed in this review are provided.
- 112Horbert, R.; Pinchuk, B.; Davies, P.; Alessi, D.; Peifer, C. Photoactivatable prodrugs of anti-melanoma agent vemurafenib. ACS Chem. Biol. 2015, 10, 2099– 107, DOI: 10.1021/acschembio.5b00174[ACS Full Text], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVShtb%252FM&md5=5eabb1cd8a1b5d5af1709052f897552fPhotoactivatable Prodrugs of Antimelanoma Agent VemurafenibHorbert, Rebecca; Pinchuk, Boris; Davies, Paul; Alessi, Dario; Peifer, ChristianACS Chemical Biology (2015), 10 (9), 2099-2107CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clin. studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of mols. triggered by UV light. Thus, higher inhibitor concns. in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacol. tools. We investigated their photochem. characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biol. tool for novel pharmacol. approaches in cancer research.
- 113Bliman, D.; Nilsson, J. R.; Kettunen, P.; Andréasson, J.; Grøtli, M. A Caged ret kinase inhibitor and its effect on motoneuron development in zebrafish embryos. Sci. Rep. 2015, 5, 13109, DOI: 10.1038/srep13109[Crossref], [PubMed], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVKht7zN&md5=390c153f289b4be85737a6cfb6e53a57A Caged Ret Kinase Inhibitor and its Effect on Motoneuron Development in Zebrafish EmbryosBliman, David; Nilsson, Jesper R.; Kettunen, Petronella; Andreasson, Joakim; Groetli, MortenScientific Reports (2015), 5 (), 13109CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)Proto-oncogene tyrosine-protein kinase receptor RET is implicated in the development and maintenance of neurons of the central and peripheral nervous systems. Attaching activity-compromising photocleavable groups (caging) to inhibitors could allow for external spatiotemporally controlled inhibition using light, potentially providing novel information on how these kinase receptors are involved in cellular processes. Here, caged RET inhibitors were obtained from 3-substituted pyrazolopyrimidine-based compds. by attaching photolabile groups to the exocyclic amino function. The most promising compd. displayed excellent inhibitory effect in cell-free, as well as live-cell assays upon decaging. Furthermore, inhibition could be efficiently activated with light in vivo in zebrafish embryos and was shown to effect motoneuron development.
- 114Zindler, M.; Pinchuk, B.; Renn, C.; Horbert, R.; Döbber, A.; Peifer, C. Design, synthesis, and characterization of a photoactivatable caged prodrug of imatinib. ChemMedChem 2015, 10, 1335– 1338, DOI: 10.1002/cmdc.201500163[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXpvFShsbk%253D&md5=2e3389a68aab1816088677fd68cc5981Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of ImatinibZindler, Melanie; Pinchuk, Boris; Renn, Christian; Horbert, Rebecca; Doebber, Alexander; Peifer, ChristianChemMedChem (2015), 10 (8), 1335-1338CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Imatinib is the first protein kinase inhibitor approved for clin. use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by UV light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacol. tool to study the impact of imatinib toward biol. systems in greater detail.
- 115Ieda, N.; Yamada, S.; Kawaguchi, M.; Miyata, N.; Nakagawa, H. (7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activity. Bioorg. Med. Chem. 2016, 24, 2789– 2793, DOI: 10.1016/j.bmc.2016.04.042[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntFCmt78%253D&md5=1428b487a0fa01f669c3a8b9433a84db(7-Diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid as a caged inhibitor for photocontrol of histone deacetylase activityIeda, Naoya; Yamada, Sota; Kawaguchi, Mitsuyasu; Miyata, Naoki; Nakagawa, HidehikoBioorganic & Medicinal Chemistry (2016), 24 (12), 2789-2793CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Histone deacetylases (HDACs) are involved in epigenetic control of the expression of various genes by catalyzing deacetylation of ε-acetylated lysine residues. Here, we report the design, synthesis and evaluation of the (7-diethylaminocoumarin-4-yl)methyl ester of suberoylanilide hydroxamic acid (AC-SAHA) as a caged HDAC inhibitor, which releases the known pan-HDAC inhibitor SAHA upon cleavage of the photolabile (7-diethylaminocoumarin-4-yl)methyl protecting group in response to photoirradn. A key advantage of AC-SAHA is that the caged deriv. itself shows essentially no HDAC-inhibitory activity. Upon photoirradn., AC-SAHA decomps. to SAHA and a 7-diethylaminocoumarin deriv., together with some minor products. We confirmed that AC-SAHA inhibits HDAC in response to photoirradn. in vitro by means of chemiluminescence assay. AC-SAHA also showed photoinduced inhibition of proliferation of human colon cancer cell line HCT116, as detd. by MTT assay. Thus, AC-SAHA should be a useful tool for spatiotemporally controlled inhibition of HDAC activity, as well as a candidate chemotherapeutic reagent for human colon cancer.
- 116Parasar, B.; Chang, P. V. Chemical optogenetic modulation of inflammation and immunity. Chem. Sci. 2017, 8, 1450– 1453, DOI: 10.1039/C6SC03702J[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslalsbfJ&md5=f03308c8d733e0defb03e41032440547Chemical optogenetic modulation of inflammation and immunityParasar, Bibudha; Chang, Pamela V.Chemical Science (2017), 8 (2), 1450-1453CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)The immune system is an essential component of host defense against pathogens and is largely mediated by inflammatory mols. produced by immune cells, such as macrophages. These inflammatory mediators are regulated at the transcriptional level by chromatin-modifying enzymes including histone deacetylases (HDACs). Here we describe a strategy to regulate inflammation and immunity with photocontrolled HDAC inhibitors, which can be selectively delivered to target cells by UV irradn. to minimize off-target effects. We strategically photocaged the active moiety of an HDAC inhibitor and showed that mild UV irradn. leads to the selective release of the inhibitor in a spatiotemporal manner. This methodol. was used to decrease the amt. of pro-inflammatory mediators produced by a subpopulation of macrophages. Our approach could ultimately be used to control inflammation in vivo as a therapeutic for inflammatory diseases, while minimizing off-target effects to healthy tissues.
- 117Tamura, R.; Balabanova, A.; Frakes, S. A.; Bargmann, A.; Grimm, J.; Koch, T. H.; Yin, H. H. Photoactivatable prodrug of doxazolidine targeting exosomes. J. Med. Chem. 2019, 62, 1959, DOI: 10.1021/acs.jmedchem.8b01508[ACS Full Text], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitlChuro%253D&md5=777f4de98d7562f37c15faa99fdf19aaPhotoactivatable Prodrug of Doxazolidine Targeting ExosomesTamura, Ryo; Balabanova, Alla; Frakes, Samuel A.; Bargmann, Austin; Grimm, Jan; Koch, Tad H.; Yin, HangJournal of Medicinal Chemistry (2019), 62 (4), 1959-1970CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Natural lipid nanocarriers, exosomes, carry cell-signaling materials such as DNA and RNA for intercellular communications. Exosomes derived from cancer cells contribute to the progression and metastasis of cancer cells by transferring oncogenic signaling mols. to neighboring and remote premetastatic sites. Therefore, applying the unique properties of exosomes for cancer therapy has been expected in science, medicine, and drug discovery fields. Herein, we report that an exosome-targeting prodrug system, designated MARCKS-ED-photodoxaz, could spatiotemporally control the activation of an exquisitely cytotoxic agent, doxazolidine (doxaz), with UV light. The MARCKS-ED peptide enters a cell by forming a complex with the exosomes in situ at its plasma membrane and in the media. MARCKS-ED-photodoxaz releases doxaz under near-UV irradn. to inhibit cell growth with low nanomolar IC50 values. The MARCKS-ED-photodoxaz system targeting exosomes and utilizing photochem. will potentially provide a new approach for the treatment of cancer, esp. for highly progressive and invasive metastatic cancers.
- 118Döbber, A.; Phoa, A. F.; Abbassi, R. H.; Stringer, B. W.; Day, B. W.; Johns, T. G.; Abadleh, M.; Peifer, C.; Munoz, L. Development and biological evaluation of a photoactivatable small molecule microtubule-targeting agent. ACS Med. Chem. Lett. 2017, 8, 395– 400, DOI: 10.1021/acsmedchemlett.6b00483[ACS Full Text], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkt1Ohsrw%253D&md5=d9b653c1d7c8a093f35d840f245ece6dDevelopment and Biological Evaluation of a Photoactivatable Small Molecule Microtubule-Targeting AgentDobber, Alexander; Phoa, Athena F.; Abbassi, Ramzi H.; Stringer, Brett W.; Day, Bryan W.; Johns, Terrance G.; Abadleh, Mohammed; Peifer, Christian; Munoz, LenkaACS Medicinal Chemistry Letters (2017), 8 (4), 395-400CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Abstr.: Photoremovable protecting groups added to bioactive mols. provide spatial and temporal control of the biol. effects. We present synthesis and characterization of the first photoactivatable small-mol. tubulin inhibitor. By blocking the pharmacophoric OH group on compd. 1 with photoremovable 4,5-dimethoxy-2-nitrobenzyl moiety we developed the photo-caged prodrug 2 that had no effect in biol. assays. Short UV light exposure of the deriv. 2 or UV-irradn. of cells treat-ed with 2 resulted in fast and potent inhibition of tubulin polymn., attenuation of cell viability and apoptotic cell death, i.m.-plicating release of the parent active compd. This study validates for the first time the photoactivatable prodrug concept in the field of small mol. tubulin inhibitors. The caged deriv. 2 represents a novel tool in anti-tubulin approaches.
- 119Perdicakis, B.; Montgomery, H. J.; Abbott, G. L.; Fishlock, D.; Lajoie, G. A.; Guillemette, J. G.; Jervis, E. Photocontrol of nitric oxide production in cell culture using a caged isoform selective inhibitor. Bioorg. Med. Chem. 2005, 13, 47– 57, DOI: 10.1016/j.bmc.2004.10.002[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2cngvVaisg%253D%253D&md5=09a25f1bedf1dceb58123f0aeb690a73Photocontrol of nitric oxide production in cell culture using a caged isoform selective inhibitorPerdicakis Basil; Montgomery Heather J; Abbott Glenn L; Fishlock Dan; Lajoie Gilles A; Guillemette J Guy; Jervis EricBioorganic & medicinal chemistry (2005), 13 (1), 47-57 ISSN:0968-0896.Over the past decade, multiphoton microscopy has progressed from a photonic novelty to a technique whose application is currently experiencing exponential growth in the biological sciences. A novel application of this technology with significant therapeutic potential is the control of drug activity by multiphoton photolysis of caged therapeutics. As an initial case study, the potent isoform selective inhibitor N-(3-(aminomethyl)benzyl) acetamidine (1400W) of inducible nitric oxide synthase (iNOS) has been conjugated to a caging molecule 6-bromo-7-hydroxy-4-hydroxyquinoline-2-ylmethyl acetyl ester (Bhc). Here we present the first report of a bulk therapeutic effect, inhibition of nitric oxide production, in mammalian cell culture by multiphoton photolysis of a caged drug, Bhc-1400W. Mouse macrophage RAW 264.7 cells induced with bacterial lipopolysaccharides to express iNOS were used to assess the therapeutic value of the conjugated inhibitor. Both 1400W and Bhc-1400W are stable in metabolically active cells and an optimal time interval for the photorelease of the inhibitor was determined. The ratios of the IC(50) values of Bhc-1400W over 1400W calculated in the presence of iNOS enzyme and in RAW 264.7 cell culture are 19 and 100, respectively, indicating that a broad therapeutic range exists in cell culture. Multiphoton uncaging protocols and therapeutic doses of inhibitors were not cytotoxic. Photocontrol of LPS induced nitric oxide production was achieved in mammalian cell culture using a single laser focal volume. This technology has the potential to control active drug concentrations in vivo, a lack of which is one of the main problems currently associated with systemic drug administration.
- 120Abrahamse, H.; Hamblin, M. R. New photosensitizers for photodynamic therapy. Biochem. J. 2016, 473, 347– 364, DOI: 10.1042/BJ20150942[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xitleqsrc%253D&md5=9ad9b594476ad2c3452189212f0827b7New photosensitizers for photodynamic therapyAbrahamse, Heidi; Hamblin, Michael R.Biochemical Journal (2016), 473 (4), 347-364CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochem. reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compds. have received clin. approval. Other mol. structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnol. has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochem. internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.
- 121Detty, M. R.; Gibson, S. L.; Wagner, S. J. Current clinical and preclinical photosensitizers for use in photodynamic therapy. J. Med. Chem. 2004, 47, 3897– 3915, DOI: 10.1021/jm040074b[ACS Full Text], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXkvFyht7c%253D&md5=6a04a3f30fc9028e9c49cce437fcc976Current Clinical and Preclinical Photosensitizers for Use in Photodynamic TherapyDetty, Michael R.; Gibson, Scott L.; Wagner, Stephen J.Journal of Medicinal Chemistry (2004), 47 (16), 3897-3915CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review, on the current clin. and preclin. photosensitizers use for PDT.
- 122Hirohara, S.; Oka, C.; Totani, M.; Obata, M.; Yuasa, J.; Ito, H.; Tamura, M.; Matsui, H.; Kakiuchi, K.; Kawai, T.; Kawaichi, M.; Tanihara, M. Synthesis, photophysical properties, and biological evaluation of trans-bisthioglycosylated tetrakis(fluorophenyl)chlorin for photodynamic therapy. J. Med. Chem. 2015, 58, 8658– 8670, DOI: 10.1021/acs.jmedchem.5b01262[ACS Full Text], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Cgu77K&md5=abe9b3cc968e56f3118692e3761d5ca7Synthesis, Photophysical Properties, and Biological Evaluation of trans-bisthioglycosylated Tetrakis(fluorophenyl)chlorin for Photodynamic TherapyHirohara, Shiho; Oka, Chio; Totani, Masayasu; Obata, Makoto; Yuasa, Junpei; Ito, Hiromu; Tamura, Masato; Matsui, Hirofumi; Kakiuchi, Kiyomi; Kawai, Tsuyoshi; Kawaichi, Masashi; Tanihara, MasaoJournal of Medicinal Chemistry (2015), 58 (21), 8658-8670CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Trans-bisthioglycosylated tetrakis(fluorophenyl)chlorin (7) was designed as a powerful photodynamic therapy (PDT) photosensitizer based on the findings of our systematic studies. We show here that the trans-bisthioglycosylated structure of 7 enhanced its uptake by HeLa cells and that the chlorin ring of 7 increased the efficiency of reactive oxygen species generation under the std. condition of our photocytotoxicity test. The versatility of 7 in PDT treatment was established using weakly metastatic B16F1 melanoma cells, metastatic 4T1 breast cancer cells, the RGK-1 gastric carcinoma mucosal cell line, and three human glioblastoma cell lines (U87, U251, and T98G). The pharmacokinetics of 7 in mice bearing 4T1 breast cancer cells showed a high tumor-to-skin concn. ratio (approx. 60) at 24 h after i.p. injection. The PDT efficacy of 7 in vivo was approx. 250-times higher than that of mono-L-aspartyl chlorin e6 (9) in mice bearing 4T1 breast cancer cells.
- 123Monro, S.; Colón, K. L.; Yin, H.; Roque, J., 3rd.; Konda, P.; Gujar, S.; Thummel, R. P.; Lilge, L.; Cameron, C. G.; McFarland, S. A. Transition metal complexes and photodynamic therapy from a tumor-centered approach: challenges, opportunities, and highlights from the development of TLD1433. Chem. Rev. 2019, 119, 797, DOI: 10.1021/acs.chemrev.8b00211[ACS Full Text], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVGmtrjK&md5=73b333b327b1f83a6146b321dfe80ba9Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433Monro, Susan; Colon, Katsuya L.; Yin, Huimin; Roque, John; Konda, Prathyusha; Gujar, Shashi; Thummel, Randolph P.; Lilge, Lothar; Cameron, Colin G.; McFarland, Sherri A.Chemical Reviews (Washington, DC, United States) (2019), 119 (2), 797-828CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)Transition metal complexes are of increasing interest as photosensitizers in photodynamic therapy (PDT) and, more recently, for photochemotherapy (PCT). In recent years, Ru(II) polypyridyl complexes have emerged as promising systems for both PDT and PCT. Their rich photochem. and photophys. properties derive from a variety of excited-state electronic configurations accessible with visible and near-IR light, and these properties can be exploited for both energy- and electron-transfer processes that can yield highly potent oxygen-dependent and/or oxygen-independent photobiol. activity. Selected examples highlight the use of rational design in coordination chem. to control the lowest-energy triplet excited-state configurations for eliciting a particular type of photoreactivity for PDT and/or PCT effects. These principles are also discussed in the context of the development of TLD1433, the first Ru(II)-based photosensitizer for PDT to enter a human clin. trial. The design of TLD1433 arose from a tumor-centered approach, as part of a complete PDT package that includes the light component and the protocol for treating non-muscle invasive bladder cancer. Briefly, this review summarizes the challenges to bringing PDT into mainstream cancer therapy. It considers the chem. and photophys. solns. that transition metal complexes offer, and it puts into context the multidisciplinary effort needed to bring a new drug to clin. trial.
- 124Xu, P.; Jia, Y.; Yang, Y.; Chen, J.; Hu, P.; Chen, Z.; Huang, M. Photodynamic oncotherapy mediated by gonadotropin-releasing hormone receptors. J. Med. Chem. 2017, 60, 8667– 8672, DOI: 10.1021/acs.jmedchem.7b01216[ACS Full Text], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFyru7vO&md5=e26279d67fc76a1603906ee59a9cc668Photodynamic Oncotherapy Mediated by Gonadotropin-Releasing Hormone ReceptorsXu, Peng; Jia, Yuhua; Yang, Yongshuai; Chen, Jincan; Hu, Ping; Chen, Zhuo; Huang, MingdongJournal of Medicinal Chemistry (2017), 60 (20), 8667-8672CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we report photodynamic oncotherapies mediated by gonadotropin-releasing hormone (GnRH) receptors. We synthesized conjugates 1 and 2 by coupling zinc phthalocyanine (ZnPc) to GnRH analogs. Compared to unmodified ZnPc, conjugates 1 and 2 exhibited higher and more specific phototoxicities to breast cancer cells. Furthermore, the two conjugates demonstrated excellent antitumor efficacies in a breast cancer-grafted animal model. Biodistribution study suggested the high biosafety of conjugate 2 because of the low retention in brain and skin.
- 125Thapa, P.; Li, M.; Bio, M.; Rajaputra, P.; Nkepang, G.; Sun, Y.; Woo, S.; You, Y. Far-red light-activatable prodrug of paclitaxel for the combined effects of photodynamic therapy and site-specific paclitaxel chemotherapy. J. Med. Chem. 2016, 59, 3204– 3214, DOI: 10.1021/acs.jmedchem.5b01971[ACS Full Text], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktFejtr4%253D&md5=0e70718577b2b60c93e9f2e3d150b70bFar-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel ChemotherapyThapa, Pritam; Li, Mengjie; Bio, Moses; Rajaputra, Pallavi; Nkepang, Gregory; Sun, Yajing; Woo, Sukyung; You, YoungjaeJournal of Medicinal Chemistry (2016), 59 (7), 3204-3214CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepd. the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymn. enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clin. useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.
- 126Battah, S.; Hider, R. C.; MacRobert, A. J.; Dobbin, P. S.; Zhou, T. Hydroxypyridinone and 5-aminolaevulinic acid conjugates for photodynamic therapy. J. Med. Chem. 2017, 60, 3498– 3510, DOI: 10.1021/acs.jmedchem.7b00346[ACS Full Text], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXlsVygtrc%253D&md5=0f83ed82793fce2ed87174a12276347aHydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic TherapyBattah, Sinan; Hider, Robert C.; MacRobert, Alexander J.; Dobbin, Paul S.; Zhou, TaoJournal of Medicinal Chemistry (2017), 60 (8), 3498-3510CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Photodynamic therapy (PDT) is a promising treatment strategy for malignant and non-malignant lesions. 5-Aminolevulinic acid (ALA) is used has a precursor of the photosensitizer, protoporphyrin IX (PpIX) in dermatol. and urol. However, the effectiveness of ALA-PDT is limited by the relatively poor bioavailability of ALA and rapid conversion of PpIX to haem. The main goal of this study was to prep. and investigate a library of single conjugates designed to co-administer the bioactive agents ALA and hydroxypyridinone (HPO) iron chelators. A significant increase in intracellular PpIX levels was obsd. in all cell lines tested when compared to the administration of ALA alone. The higher PpIX levels obsd. using the conjugates correlated well with the obsd. phototoxicity following exposure of cells to light. Passive diffusion appears to be the main mechanism for the majority of ALA-HPOs investigated. This study demonstrates that ALA-HPOs significantly enhance phototherapeutic metabolite formation and phototoxicity.
- 127Feng, X.; Shi, Y.; Xie, L.; Zhang, K.; Wang, X.; Liu, Q.; Wang, P. Synthesis, characterization, and biological evaluation of a porphyrin-based photosensitizer and its isomer for effective photodynamic therapy against breast cancer. J. Med. Chem. 2018, 61, 7189– 7201, DOI: 10.1021/acs.jmedchem.8b00547[ACS Full Text], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2htbnJ&md5=1cc188053e3eb02466acad3f1b1cffd4Synthesis, Characterization, and Biological Evaluation of a Porphyrin-Based Photosensitizer and Its Isomer for Effective Photodynamic Therapy against Breast CancerFeng, Xiaolan; Shi, Yin; Xie, Lifen; Zhang, Kun; Wang, Xiaobing; Liu, Quanhong; Wang, PanJournal of Medicinal Chemistry (2018), 61 (16), 7189-7201CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A photosensitizer with high phototoxicity, low dark toxicity, and good water soly. is crucial for effective photodynamic therapy (PDT). In this study, a novel class of porphyrin-based water-sol. deriv. and its isomers, named photohexer-1 (P-1) and photohexer-2 (P-2), were synthesized and investigated for anticancer activity. Both of the isomers, P-1 and P-2, could be utilized as potential sensitizers for PDT not only owing to their definite constituents but predominantly due to their good absorption in the phototherapeutic window and high generation of intracellular ROS. Therein, P-2 exhibited stronger phototoxicity against breast cancer cells with weaker dark toxicity than P-1; however, both P-1 and P-2 were highly phototoxic as compared to their homologous compd., hematoporphyrin monomethyl ether (HMME). These findings were consistent with the antitumor efficacy in vivo. Moreover, P-1 and P-2 could both effectively localize in multiple subcellular organelles, triggering increased cellular apoptosis or necrosis under laser irradn. as compared to HMME. In conclusion, the findings of the study suggest that the two highly water-sol. porphyrin derivs. may serve as promising putative photosensitizers for improving the therapeutic efficiency of PDT.
- 128Zhou, Y.; Cheung, Y. K.; Ma, C.; Zhao, S.; Gao, D.; Lo, P. C.; Fong, W. P.; Wong, K. S.; Ng, D. K. P. Endoplasmic reticulum-localized two-photon-absorbing boron dipyrromethenes as advanced photosensitizers for photodynamic therapy. J. Med. Chem. 2018, 61, 3952– 3961, DOI: 10.1021/acs.jmedchem.7b01907[ACS Full Text], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVahtLs%253D&md5=2eff962be9e0a9c09331d6ab95a7c9d3Endoplasmic Reticulum-Localized Two-Photon-Absorbing Boron Dipyrromethenes as Advanced Photosensitizers for Photodynamic TherapyZhou, Yimin; Cheung, Ying-Kit; Ma, Chao; Zhao, Shirui; Gao, Di; Lo, Pui-Chi; Fong, Wing-Ping; Wong, Kam Sing; Ng, Dennis K. P.Journal of Medicinal Chemistry (2018), 61 (9), 3952-3961CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two advanced boron dipyrromethene (BODIPY) based photosensitizers have been synthesized and characterized. With a glibenclamide analogous moiety, these compds. can localize in the endoplasmic reticulum (ER) of HeLa human cervical carcinoma cells and HepG2 human hepatocarcinoma cells. The BODIPY π skeleton is conjugated with two styryl or carbazolylethenyl groups, which can substantially red-shift the Q-band absorption and fluorescence emission and impart two-photon absorption (TPA) property to the chromophores. The TPA cross section of the carbazole-contg. analog reaches a value of 453 GM at 1010 nm. These compds. also behave as singlet oxygen generators with high photostability. Upon irradn. at λ > 610 nm, these photosensitizers cause photocytotoxicity to these two cell lines with IC50 values down to 0.09 μM, for which the cell death is triggered mainly by ER stress. The two-photon photodynamic activity of the distyryl deriv. upon excitation at λ = 800 nm has also been demonstrated.
- 129Cheruku, R. R.; Cacaccio, J.; Durrani, F.; Tabaczynski, W. A.; Watson, R.; Marko, A. J.; Kumar, R.; El-Khouly, M. E.; Fukuzumi, S.; Missert, J. R.; Yao, R.; Sajjad, M.; Chandra, D.; Guru, K.; Pandey, R. K. Epidermal growth factor receptor targeted multifunctional photosensitizers for bladder cancer imaging and photodynamic therapy. J. Med. Chem. 2019, 62, 2598, DOI: 10.1021/acs.jmedchem.8b01927[ACS Full Text], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFGjsrg%253D&md5=2b6d6c1387d3d847f9a0be8b3f8ee1b1Epidermal Growth Factor Receptor-Targeted Multifunctional Photosensitizers for Bladder Cancer Imaging and Photodynamic TherapyCheruku, Ravindra R.; Cacaccio, Joseph; Durrani, Farukh A.; Tabaczynski, Walter A.; Watson, Ramona; Marko, Aimee; Kumar, Rahul; El-Khouly, Mohamed E.; Fukuzumi, Shunichi; Missert, Joseph R.; Yao, Rutao; Sajjad, Munawwar; Chandra, Dhyan; Guru, Khurshid; Pandey, Ravindra K.Journal of Medicinal Chemistry (2019), 62 (5), 2598-2617CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The in vitro and in vivo anticancer activity of iodinated photosensitizers (PSs) with and without an erlotinib moiety was investigated in UMUC3 [epidermal growth factor (EGFR)-pos.] and T24 (EGFR-low) cell lines and tumored mice. Both the erlotinib-conjugated PSs 3 and 5 showed EGFR target specificity, but the position-3 erlotinib-PS conjugate 3 demonstrated lower photodynamic therapy efficacy than the corresponding non-erlotinib analog 1, whereas the conjugate 5 contg. an erlotinib moiety at position-17 of the PS showed higher tumor uptake and long-term tumor cure (severe combined immunodeficient mice bearing UMUC3 tumors). PS-erlotinib conjugates in the absence of light were ineffective in vitro and in vivo, but robust apoptotic and necrotic cell death was obsd. in bladder cancer cells after exposing them to a laser light at 665 nm. In contrast to 18F-fluorodeoxyglucose, a positron emission tomog. agent, the position-17 erlotinib conjugate (124I-analog 6) showed enhanced UMUC3 tumor contrast even at a low imaging dose of 15 μCi/mouse.
- 130Blacklock, K. M.; Yachnin, B. J.; Woolley, G. A.; Khare, S. D. Computational design of a photocontrolled cytosine deaminase. J. Am. Chem. Soc. 2018, 140, 14– 17, DOI: 10.1021/jacs.7b08709[ACS Full Text], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvF2gsL%252FL&md5=0f8919b263b38a015857fc60b09a2eb8Computational design of a photocontrolled cytosine deaminaseBlacklock, Kristin M.; Yachnin, Brahm J.; Woolley, G. Andrew; Khare, Sagar D.Journal of the American Chemical Society (2018), 140 (1), 14-17CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)There is growing interest in designing spatiotemporal control over enzyme activities using noninvasive stimuli such as light. Here, we describe a structure-based, computation-guided predictive method for reversibly controlling enzyme activity using covalently attached photoresponsive azobenzene groups. Applying the method to the therapeutically useful enzyme yeast cytosine deaminase, we obtained a ∼3-fold change in enzyme activity by the photocontrolled modulation of the enzyme's active site lid structure, while fully maintaining thermostability. Multiple cycles of switching, controllable in real time, are possible. The predictiveness of the method is demonstrated by the construction of a variant that does not photoswitch as expected from computational modeling. Our design approach opens new avenues for optically controlling enzyme function. The designed photocontrolled cytosine deaminases may also aid in improving chemotherapy approaches that utilize this enzyme.
- 131Zhu, M.; Zhou, H. Azobenzene-based small molecular photoswitches for protein modulation. Org. Biomol. Chem. 2018, 16, 8434– 8445, DOI: 10.1039/C8OB02157K[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVaqtbfJ&md5=889c70a0d1443631db1125f9d9364881Azobenzene-based small molecular photoswitches for protein modulationZhu, Mingyan; Zhou, HuchenOrganic & Biomolecular Chemistry (2018), 16 (44), 8434-8445CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)A review. Mol. photoswitches are a class of chem. structures that can readily isomerize between distinct geometries upon irradn. with light. Mol. photoswitches are utilized to control protein structure and function with temporal and spatial precision. In this review, we summarize the recent progress in the development of azobenzene-based mol. photoswitches and their applications in the photocontrol of protein structure and function. For clarity of discussion, we divide the known photoswitchable proteins into different categories: protein motifs, ion channels, receptors, and enzymes. Basic approaches and considerations for the structure-guided design of photoswitchable ligands are discussed. The applications and limitations of current photoswitches are also discussed.
- 132(a) Quandt, G.; Höfner, G.; Pabel, J.; Dine, J.; Eder, M.; Wanner, K. T. First photoswitchable neurotransmitter transporter inhibitor: light-induced control of γ-aminobutyric acid transporter 1 (GAT1) activity in mouse brain. J. Med. Chem. 2014, 57, 6809– 6821, DOI: 10.1021/jm5008566[ACS Full Text.], [CAS], Google Scholar132ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFCrtL3E&md5=a0887de793bab7d481d46db4c4ea88f7First Photoswitchable Neurotransmitter Transporter Inhibitor: Light-Induced Control of γ-Aminobutyric Acid Transporter 1 (GAT1) Activity in Mouse BrainQuandt, Gabriele; Hoefner, Georg; Pabel, Joerg; Dine, Julien; Eder, Matthias; Wanner, Klaus T.Journal of Medicinal Chemistry (2014), 57 (15), 6809-6821CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be assocd. with low GABA levels. We have now developed a potent and subtype selective photoswitchable inhibitor of this transporter, which for the first time extends the photoswitch concept for the light-induced control of ligand affinity to active membrane transporters. The new inhibitor exhibited reduced activity upon irradn. with light, as demonstrated in GABA uptake assays and electrophysiol. expts. with brain slices, and might be used as a tool compd. for deepening the understanding of mGAT1 function in brain.(b) Lutz, T.; Wein, T.; Höfner, G.; Pabel, J.; Eder, M.; Dine, J.; Wanner, K. T. Development of new photoswitchable azobenzene based γ-aminobutyric acid (GABA) uptake inhibitors with distinctly enhanced potency upon photoactivation. J. Med. Chem. 2018, 61, 6211– 6235, DOI: 10.1021/acs.jmedchem.8b00629[ACS Full Text], [CAS], Google Scholar132bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFyjs7rJ&md5=3266bef7983c46e3dd4e53b3ae2c9f6aDevelopment of New Photoswitchable Azobenzene Based γ-Aminobutyric Acid (GABA) Uptake Inhibitors with Distinctly Enhanced Potency upon PhotoactivationLutz, Toni; Wein, Thomas; Hoefner, Georg; Pabel, Joerg; Eder, Matthias; Dine, Julien; Wanner, Klaus T.Journal of Medicinal Chemistry (2018), 61 (14), 6211-6235CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of nipecotic acid derivs. with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at γ-aminobutyric acid transporters subtype 1 (GAT1), the most common γ-aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradn. For the most efficient photoactivatable nipecotic acid deriv. displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 ± 0.05 (pIC50) was found for its (E)-form. which increased by almost two log units up to 6.38 ± 0.04 when irradiated. The effect of this photoswitchable mGAT1 inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.
- 133Nørager, N. G.; Poulsen, M. H.; Strømgaard, K. Controlling Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors with photochromic ion channel blockers. J. Med. Chem. 2018, 61, 8048– 8053, DOI: 10.1021/acs.jmedchem.8b00756[ACS Full Text], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7pvVemtg%253D%253D&md5=d18ecb8d74f1f1dc69a713a8fc4f44abControlling Ca(2+) Permeable α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Photochromic Ion Channel BlockersNorager Niels G; Poulsen Mette H; Stromgaard KristianJournal of medicinal chemistry (2018), 61 (17), 8048-8053 ISSN:.Ionotropic glutamate receptors (iGluRs) play a critical role in normal brain function and neurodegenerative diseases. Development of light-dependent compounds would enable studies of iGluRs within intact mammalian neural tissue, as light is noninvasive and can be applied with high spatiotemporal precision. Here we develop a potent photochromic antagonist that selectively targets the Ca(2+) permeable AMPA-type of iGuRs, thus providing an important tool to study the contribution of AMPA-type iGluRs on neuronal activity.
- 134Matera, C.; Gomila, A. M. J.; Camarero, N.; Libergoli, M.; Soler, C.; Gorostiza, P. Photoswitchable antimetabolite for targeted photoactivated chemotherapy. J. Am. Chem. Soc. 2018, 140, 15764– 15773, DOI: 10.1021/jacs.8b08249[ACS Full Text], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvV2rs77L&md5=72c17ae2b4c36e10e72f9485bc851091Photoswitchable Antimetabolite for Targeted Photoactivated ChemotherapyMatera, Carlo; Gomila, Alexandre M. J.; Camarero, Nuria; Libergoli, Michela; Soler, Concepcio; Gorostiza, PauJournal of the American Chemical Society (2018), 140 (46), 15764-15773CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficacy and tolerability of systemically administered anticancer agents are limited by their off-target effects. Precise spatiotemporal control over their cytotoxic activity would allow improving chemotherapy treatments, and light-regulated drugs are well suited to this purpose. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase (DHFR), as a photochromic analog of methotrexate, a widely prescribed chemotherapeutic drug to treat cancer and psoriasis. Quantification of the light-regulated DHFR enzymic activity, cell proliferation, and in vivo effects in zebrafish show that phototrexate behaves as a potent antifolate in its photoactivated cis configuration and that it is nearly inactive in its dark-relaxed trans form. Thus, phototrexate constitutes a proof-of-concept to design light-regulated cytotoxic small mols. and a step forward to develop targeted anticancer photochemotherapies with localized efficacy and reduced adverse effects.
- 135Li, J.; Kong, H.; Huang, L.; Cheng, B.; Qin, K.; Zheng, M.; Yan, Z.; Zhang, Y. Visible light-initiated bioorthogonal photoclick cycloaddition. J. Am. Chem. Soc. 2018, 140, 14542– 14546, DOI: 10.1021/jacs.8b08175[ACS Full Text], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvF2mt7%252FI&md5=40821844ee74b4194ea983b7cbf4ff89Visible Light-Initiated Bioorthogonal Photoclick CycloadditionLi, Jinbo; Kong, Hao; Huang, Lei; Cheng, Bo; Qin, Ke; Zheng, Mengmeng; Yan, Zheng; Zhang, YanJournal of the American Chemical Society (2018), 140 (44), 14542-14546CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Here we report a visible light-triggered, catalyst free bioorthogonal reaction that proceeds via a distinct pathway from reported bioorthogonal reactions. The prototype of this bioorthogonal reaction was the photocycloaddn. of 9,10-phenanthrenequinone with electron-rich alkenes to form fluorogenic [4+2] cycloadducts. The bioorthogonal photoclick cycloaddn. was readily initiated using a conventional visible light source such as a hand-held LED lamp. The reaction proceeded rapidly under biocompatible conditions, without observable competition from side reactions such as nucleophilic addns. by water or common nucleophilic species. The bioorthogonal functionality in this reaction did not cross react with various alkynes and electron-deficient alkenes such as monomethyl fumarate. We demonstrated orthogonal labeling of two proteins using this reaction together with a strain promoting azide-alkyne click reaction or the UV-triggered reaction of tetrazole with monomethyl fumarate. The application of this reaction in the temporal and spatial labeling of live cells was also demonstrated.
- 136Comer, E.; Beaudoin, J. A.; Kato, N.; Fitzgerald, M. E.; Heidebrecht, R. W.; Lee, Md, 4th.; Masi, D.; Mercier, M.; Mulrooney, C.; Muncipinto, G.; Rowley, A.; Crespo-Llado, K.; Serrano, A. E.; Lukens, A. K.; Wiegand, R. C.; Wirth, D. F.; Palmer, M. A.; Foley, M. A.; Munoz, B.; Scherer, C. A.; Duvall, J. R.; Schreiber, S. L. Diversity-oriented synthesis-facilitated medicinal chemistry: toward the development of novel antimalarial agents. J. Med. Chem. 2014, 57, 8496– 8502, DOI: 10.1021/jm500994n[ACS Full Text], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFams77O&md5=05ec57a8972d21220ccae6e57fb37664Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial AgentsComer, Eamon; Beaudoin, Jennifer A.; Kato, Nobutaka; Fitzgerald, Mark E.; Heidebrecht, Richard W.; Lee, Maurice duPont; Masi, Daniela; Mercier, Marion; Mulrooney, Carol; Muncipinto, Giovanni; Rowley, Ann; Crespo-Llado, Keila; Serrano, Adelfa E.; Lukens, Amanda K.; Wiegand, Roger C.; Wirth, Dyann F.; Palmer, Michelle A.; Foley, Michael A.; Munoz, Benito; Scherer, Christina A.; Duvall, Jeremy R.; Schreiber, Stuart L.Journal of Medicinal Chemistry (2014), 57 (20), 8496-8502CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we describe medicinal chem. that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved soly. and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the prepn. of the original screening library, facilitated medicinal chem. optimization of the antimalarial lead.
- 137Kuttruff, C. A.; Haile, M.; Kraml, J.; Tautermann, C. S. Late-stage functionalization of drug-like molecules using diversinates. ChemMedChem 2018, 13, 983– 987, DOI: 10.1002/cmdc.201800151[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotFWisbY%253D&md5=92d3e35516843c572aff18331897e0feLate-Stage Functionalization of Drug-Like Molecules Using DiversinatesKuttruff, Christian A.; Haile, Margit; Kraml, Johannes; Tautermann, Christofer S.ChemMedChem (2018), 13 (10), 983-987CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Late-stage functionalization (LSF) is a powerful method to quickly generate new analogs of a lead structure without resorting to de novo synthesis. We have leveraged Baran Diversinates to carry out late-stage functionalizations on lead structures from internal drug discovery projects and accurately predicted regioselectivities using computational methods. Our functionalization successfully afforded specific regioisomers which were in line with our predictions. To enhance reactivity, decrease reaction time, and increase reaction yields, we have developed new functionalization conditions involving iron(III) catalysis. Finally, we demonstrate how our LSF reactions using Baran Diversinates can lead to new analogs with improved in vitro DMPK parameters.
- 138Caro-Diaz, E. J. E.; Urbano, M.; Buzard, D. J.; Jones, R. M. C-H activation reactions as useful tools for medicinal chemists. Bioorg. Med. Chem. Lett. 2016, 26, 5378– 5383, DOI: 10.1016/j.bmcl.2016.06.036[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslSlsLfF&md5=ac6533ee047115f06062d46be1247881C-H activation reactions as useful tools for medicinal chemistsCaro-Diaz, Eduardo J. E.; Urbano, Mariangela; Buzard, Daniel J.; Jones, Robert M.Bioorganic & Medicinal Chemistry Letters (2016), 26 (22), 5378-5383CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. In recent years, there has been an exponential rise in the no. of reports describing synthetic methods that utilize catalytic sp3 and sp2 C-H bond activation. Many have emerged as powerful synthetic tools for accessing biol. active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chem.
- 139Sekizawa, H.; Amaike, K.; Itoh, Y.; Suzuki, T.; Itami, K.; Yamaguchi, J. Late-stage C-H coupling enables rapid identification of HDAC inhibitors: synthesis and evaluation of NCH-31 analogues. ACS Med. Chem. Lett. 2014, 5, 582– 586, DOI: 10.1021/ml500024s[ACS Full Text], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXjsVehs70%253D&md5=57848d9256b3be492fb405393567ea5fLate-Stage C-H Coupling Enables Rapid Identification of HDAC Inhibitors: Synthesis and Evaluation of NCH-31 AnaloguesSekizawa, Hiromi; Amaike, Kazuma; Itoh, Yukihiro; Suzuki, Takayoshi; Itami, Kenichiro; Yamaguchi, JunichiroACS Medicinal Chemistry Letters (2014), 5 (5), 582-586CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogs of NCH-31 with different aryl groups at the C4-position of the 2-aminothiazole core of NCH-31. Subsequent biol. testing of these derivs. revealed that 3-fluorophenyl (I) and 4-fluorophenyl (II) derivs. act as potent pan-HDAC inhibitor. Addnl., 4-methylphenyl and 3-fluoro-4-methylphenyl derivs. acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional mols.
- 140Miyamura, S.; Araki, M.; Suzuki, T.; Yamaguchi, J.; Itami, K. Stereodivergent synthesis of arylcyclopropylamines by sequential C-H borylation and Suzuki-Miyaura coupling. Angew. Chem., Int. Ed. 2015, 54, 846– 851, DOI: 10.1002/anie.201409186[Crossref], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXltVKrsA%253D%253D&md5=6e08f4a20cdcc7481b0cc1444a86f517Stereodivergent Synthesis of Arylcyclopropylamines by Sequential C-H Borylation and Suzuki-Miyaura CouplingMiyamura, Shin; Araki, Misaho; Suzuki, Takayoshi; Yamaguchi, Junichiro; Itami, KenichiroAngewandte Chemie, International Edition (2015), 54 (3), 846-851CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C(sp3)-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is obsd. under the reaction conditions. This epimerization is, however, suppressed in the presence of O2. The present new ACPA synthesis results in not only a significant redn. in the steps required for making ACPA derivs., but also the ability to access either isomer (cis or trans) by simply changing the atm. (N2 or O2) in the coupling stage.
- 141El Marrouni, A.; Campbell, M.; Perkins, J. J.; Converso, A. Development of a sp(2)-sp(3) stille cross-coupling for rapid synthesis of HIV NNRTI doravirine analogues. Org. Lett. 2017, 19, 3071– 3074, DOI: 10.1021/acs.orglett.7b01142[ACS Full Text], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpt1Kgtbc%253D&md5=4529cbaf18461b6bf22b1c80b28beba0Development of a sp2-sp3 Stille Cross-Coupling for Rapid Synthesis of HIV NNRTI Doravirine AnaloguesEl Marrouni, Abdellatif; Campbell, Mark; Perkins, James J.; Converso, AntonellaOrganic Letters (2017), 19 (12), 3071-3074CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)The development of a C(sp2)-C(sp3) cross-coupling reaction for rapid, parallel synthesis of analogs of two HIV NNRTI clin. candidates is described. This method allowed easy access to the C-ring space using a practical alkylation with com. available tributyl(iodomethyl)stannane followed by a palladium-catalyzed coupling with a variety of aryl halides (I, Br) in the presence of copper chloride. Optimization and scope of this method are reported.
- 142Naret, T.; Khelifi, I.; Provot, O.; Bignon, J.; Levaique, H.; Dubois, J.; Souce, M.; Kasselouri, A.; Deroussent, A.; Paci, A.; Varela, P. F.; Gigant, B.; Alami, M.; Hamze, A. 1,1-Diheterocyclic ethylenes derived from quinaldine and carbazole as new tubulin polymerization inhibitors: synthesis, metabolism, and biological evaluation. J. Med. Chem. 2019, 62, 1902, DOI: 10.1021/acs.jmedchem.8b01386[ACS Full Text], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVKrsbfK&md5=d03170fb8982119e7e0c51934a8500c91,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological EvaluationNaret, Timothee; Khelifi, Ilhem; Provot, Olivier; Bignon, Jerome; Levaique, Helene; Dubois, Joelle; Souce, Martin; Kasselouri, Athena; Deroussent, Alain; Paci, Angelo; Varela, Paloma F.; Gigant, Benoit; Alami, Mouad; Hamze, AbdallahJournal of Medicinal Chemistry (2019), 62 (4), 1902-1916CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)1,1-Diheteroaryl ethylenes such as I were prepd. as isocombretastatin-A4 analogs and tested for their antitumor activities and inhibition of tubulin polymn. Palladium-catalyzed coupling of the tosylhydrazones of heteroaryl Me ketones with heteroaryl halides yielded 1,1-diheteroaryl ethylenes. The antitumor activities in a panel of human cancer cell lines, the effects on angiogenesis and cell cycle advancement, metab. in rat and human liver microsomes, and calcd. physicochem. properties for selected compds. were detd. For example, I inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range and showed activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. The structure of I bound to tubulin was detd. by X-ray crystallog. I may be a possible candidate for the treatment of glioblastoma.
- 143Brown, D. G.; Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone?. J. Med. Chem. 2016, 59, 4443– 4458, DOI: 10.1021/acs.jmedchem.5b01409[ACS Full Text], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvVeqsrzM&md5=fd56ba8418f6d4e8c271f4e977ee2a93Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?Brown, Dean G.; Bostrom, JonasJournal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
- 144Fier, P. S.; Maloney, K. M. NHC-Catalyzed deamination of primary sulfonamides: a platform for late-stage functionalization. J. Am. Chem. Soc. 2019, 141, 1441, DOI: 10.1021/jacs.8b11800[ACS Full Text], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVajtbs%253D&md5=3f8d1a52927370182dd701241cce18c3NHC-Catalyzed Deamination of Primary Sulfonamides: A Platform for Late-Stage FunctionalizationFier, Patrick S.; Maloney, Kevin M.Journal of the American Chemical Society (2019), 141 (4), 1441-1445CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Primary alkyl and aryl sulfonamides underwent chemoselective deamination reactions with benzaldehyde and K2CO3 in the presence of a pyrrolotriazolium chloride via N-benzylidenesulfonamides to yield sulfinate salts; the sulfinates were converted in situ to Me and aryl sulfones, sulfonic acids, and sulfonamides. Reaction of the sulfinates with MeI in DMF yielded Me sulfones, while oxidn. with H2O2 in the presence of tungstic acid yielded sulfonic acids. Reaction of the sulfinate generated from celecoxib with 15NH4OH yielded the corresponding 15N-labeled sulfonamide; coupling reactions of the celecoxib-derived sulfinate with iodobenzene and a chloropyridine yielded aryl sulfones, while desulfonative coupling with Ph triflate yielded a biphenylpyrazole. The method tolerated nearly all common functional groups, including primary amines, and was used for the late-stage derivatization of several complex pharmaceutical compds.
- 145Uehling, M. R.; King, R. P.; Krska, S. W.; Cernak, T.; Buchwald, S. L. Pharmaceutical diversification via palladium oxidative addition complexes. Science 2019, 363, 405– 408, DOI: 10.1126/science.aac6153[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1anu7s%253D&md5=1e241f2157cd0f6dda80fe8c637b90cePharmaceutical diversification via palladium oxidative addition complexesUehling, Mycah R.; King, Ryan P.; Krska, Shane W.; Cernak, Tim; Buchwald, Stephen L.Science (Washington, DC, United States) (2019), 363 (6425), 405-408CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Palladium-catalyzed cross-coupling reactions have transformed the exploration of chem. space in the search for materials, medicines, chem. probes, and other functional mols. However, cross-coupling of densely functionalized substrates remains a major challenge. We devised an alternative approach using stoichiometric quantities of palladium oxidative addn. complexes (OACs) derived from drugs or drug-like aryl halides as substrates. In most cases, cross-coupling reactions using OACs proceed under milder conditions and with higher success than the analogous catalytic reactions. OACs exhibit remarkable stability, maintaining their reactivity after months of bench-top storage under ambient conditions. We demonstrated the utility of OACs in a variety of expts. including automated nanomole-scale couplings between an OAC derived from rivaroxaban (I) and hundreds of diverse nucleophiles, as well as the late-stage derivatization of the natural product k252a.
- 146Clark, J. R.; Feng, K.; Sookezian, A.; White, M. C. Manganese-catalysed benzylic C(sp(3))-H amination for late-stage functionalization. Nat. Chem. 2018, 10, 583– 591, DOI: 10.1038/s41557-018-0020-0[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXovVCkur4%253D&md5=37c6b2d770fabbd4b6ec6bf31d4877c6Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalizationClark, Joseph R.; Feng, Kaibo; Sookezian, Anasheh; White, M. ChristinaNature Chemistry (2018), 10 (6), 583-591CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)Reactions that directly install nitrogen into C-H bonds of complex mols. are significant because of their potential to change the chem. and biol. properties of a given compd. Although selective intramol. C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermol. C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermol. benzylic C-H amination of bioactive mols. and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Bronsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-detg. step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalyzed C-H aminations and provide new opportunities for tunable selectivities.
- 147Margrey, K. A.; Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E. J. A general strategy for aliphatic C-H functionalization enabled by organic photoredox catalysis. J. Am. Chem. Soc. 2018, 140, 4213– 4217, DOI: 10.1021/jacs.8b00592[ACS Full Text], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXktlCqt7s%253D&md5=ec9e4b9d881aa159e6cfbd02fca643beA General Strategy for Aliphatic C-H Functionalization Enabled by Organic Photoredox CatalysisMargrey, Kaila A.; Czaplyski, William L.; Nicewicz, David A.; Alexanian, Erik J.Journal of the American Chemical Society (2018), 140 (12), 4213-4217CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Synthetic transformations that functionalize unactivated aliph. C-H bonds in an intermol. fashion offer unique strategies for the synthesis and late-stage derivatization of complex mols. Herein we report a general approach to the intermol. functionalization of aliph. C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradn. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes.
- 148Laudadio, G.; Govaerts, S.; Wang, Y.; Ravelli, D.; Koolman, H. F.; Fagnoni, M.; Djuric, S. W.; Noël, T. Selective C(sp3)-H aerobic oxidation enabled by decatungstate photocatalysis in flow. Angew. Chem., Int. Ed. 2018, 57, 4078– 4082, DOI: 10.1002/anie.201800818[Crossref], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXkt1Gqu7g%253D&md5=7624e1eb218601fb8c9b94c65b9dfa1fSelective C(sp3)-H Aerobic Oxidation Enabled by Decatungstate Photocatalysis in FlowLaudadio, Gabriele; Govaerts, Sebastian; Wang, Ying; Ravelli, Davide; Koolman, Hannes F.; Fagnoni, Maurizio; Djuric, Stevan W.; Noel, TimothyAngewandte Chemie, International Edition (2018), 57 (15), 4078-4082CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A mild and selective C(sp3)-H aerobic oxidn. enabled by decatungstate photocatalysis has been developed. The reaction can be significantly improved in a microflow reactor enabling the safe use of oxygen and enhanced irradn. of the reaction mixt. Our method allows for the oxidn. of both activated and unactivated C-H bonds (30 examples). The ability to selectively oxidize natural scaffolds, such as (-)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, exemplifies the utility of this new method.
- 149Liu, Z.; Li, J.; Li, S.; Li, G.; Sharpless, K. B.; Wu, P. SuFEx click chemistry enabled late-stage drug functionalization. J. Am. Chem. Soc. 2018, 140, 2919– 2925, DOI: 10.1021/jacs.7b12788[ACS Full Text], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXivVSlu7w%253D&md5=f42bd4b58df0ae8f3ca5a03feb156b0aSuFEx Click Chemistry Enabled Late-Stage Drug FunctionalizationLiu, Zilei; Li, Jie; Li, Suhua; Li, Gencheng; Sharpless, K. Barry; Wu, PengJournal of the American Chemical Society (2018), 140 (8), 2919-2925CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chem. transformations which relies on readily available materials to produce compds. bearing the SVI-F motif. The potential of SuFEx in drug discovery has just started to be explored. The authors report the first method of SuFEx chem. for the conversion of phenolic compds. to their resp. arylfluorosulfate derivs. in situ in 96-well plates. This method is compatible with automated synthesis and screening to quickly assess the biol. activities of the in situ generated, crude products. Using this method, the authors perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates. These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors. The authors discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors. Among these three compds., the fluorosulfate deriv. of Fulvestrant possesses significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7 and the fluorosulfate deriv. of Combretastatin A4-a general anticancer drug currently being evaluated under clin. trials-exhibits a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29.
- 150Boström, J.; Brown, D. G.; Young, R. J.; Keserü, G. M. Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discovery 2018, 17, 709, DOI: 10.1038/nrd.2018.116[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3htlWisw%253D%253D&md5=d87e988602808139597576ced56faa88Expanding the medicinal chemistry synthetic toolboxBostrom Jonas; Brown Dean G; Young Robert J; Keseru Gyorgy MNature reviews. Drug discovery (2018), 17 (10), 709-727 ISSN:.The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.
- 151Roughley, S. D.; Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 2011, 54, 3451– 3479, DOI: 10.1021/jm200187y[ACS Full Text], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXlsVyhsrg%253D&md5=a94df26d82bbd58b269ed20aa3253f56The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug CandidatesRoughley, Stephen D.; Jordan, Allan M.Journal of Medicinal Chemistry (2011), 54 (10), 3451-3479CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. A survey of selected medicinal chem. literature from 2008 was undertaken in order to det. the most common chem. reactions used in the prepn. of drug candidates. In addn. to an examn. of the reactions, the frequency of occurrence of various functional groups in the drug targets was analyzed. The Lipinski parameters and chirality of the surveyed compds. were also discussed.
- 152Frédérich, M.; Pirotte, B.; Fillet, M.; de Tullio, P. Metabolomics as a challenging approach for medicinal chemistry and personalized medicine. J. Med. Chem. 2016, 59, 8649– 8666, DOI: 10.1021/acs.jmedchem.5b01335[ACS Full Text], [CAS], Google Scholar152https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XpsF2lsr4%253D&md5=b7a0f8f2559582d7489ec0270663f9c3Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized MedicineFrederich, Michel; Pirotte, Bernard; Fillet, Marianne; de Tullio, PascalJournal of Medicinal Chemistry (2016), 59 (19), 8649-8666CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)"Omics" sciences have been developed to provide a holistic point of view of biol. and to better understand the complexity of an organism as a whole. These systems biol. approaches can be examd. at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qual. and quant. study of metabolites. This emerging field is clearly linked to genomics, transcriptomics, and proteomics. In addn., metabolomics provides a unique and direct vision of the functional outcome of an organism's activities that are required for it to survive, grow, and respond to internal and external stimuli or stress, e.g., pathologies and drugs. The links between metabolic changes, patient phenotype, physiol. and/or pathol. status, and treatment are now well established and have opened a new area for the application of metabolomics in the drug discovery process and in personalized medicine.
- 153(a) Stepan, A. F.; Tran, T. P.; Helal, C. J.; Brown, M. S.; Chang, C.; O’Connor, R. E.; De Vivo, M.; Doran, S. D.; Fisher, E. L.; Jenkinson, S.; Karanian, D.; Kormos, B. L.; Sharma, R.; Walker, G. S.; Wright, A. S.; Yang, E. X.; Brodney, M. A.; Wager, T. T.; Verhoest, P. R.; Obach, R. S. Late-stage microsomal oxidation reduces drug-drug interaction and identifies phosphodiesterase 2A inhibitor PF-06815189. ACS Med. Chem. Lett. 2018, 9, 68– 72, DOI: 10.1021/acsmedchemlett.7b00343[ACS Full Text.], [CAS], Google Scholar153ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Wqsg%253D%253D&md5=86a976a3eebf2bbbb9865ae655909ab7Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189Stepan, Antonia F.; Tran, Tuan P.; Helal, Christopher J.; Brown, Maria S.; Chang, Cheng; O'Connor, Rebecca E.; De Vivo, Michael; Doran, Shawn D.; Fisher, Ethan L.; Jenkinson, Stephen; Karanian, David; Kormos, Bethany L.; Sharma, Raman; Walker, Gregory S.; Wright, Ann S.; Yang, Edward X.; Brodney, Michael A.; Wager, Travis T.; Verhoest, Patrick R.; Obach, R. ScottACS Medicinal Chemistry Letters (2018), 9 (2), 68-72CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Late-stage oxidn. using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P 450 enzymes, introduce renal clearance and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 with improved physicochem. properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.(b) Obach, R. S.; Walker, G. S.; Sharma, R.; Jenkinson, S.; Tran, T. P.; Stepan, A. F. Lead diversification at the nanomole scale using liver microsomes and quantitative nuclear magnetic resonance spectroscopy: application to phosphodiesterase 2 inhibitors. J. Med. Chem. 2018, 61, 3626– 3640, DOI: 10.1021/acs.jmedchem.8b00116[ACS Full Text], [CAS], Google Scholar153bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXms1artbs%253D&md5=10c4e199e4c58bd90661851fdc3bc1a6Lead Diversification at the Nanomole Scale Using Liver Microsomes and Quantitative Nuclear Magnetic Resonance Spectroscopy: Application to Phosphodiesterase 2 InhibitorsObach, R. Scott; Walker, Gregory S.; Sharma, Raman; Jenkinson, Stephen; Tran, Tuan P.; Stepan, Antonia F.Journal of Medicinal Chemistry (2018), 61 (8), 3626-3640CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In this report, we describe a method whereby lead mols. can be converted into several new analogs each using liver microsomes. Less than one micromole of substrate is incubated with liver microsomes (mouse, rat, hamster, guinea pig, rabbit, dog, monkey, or human) to produce multiple products which are isolated and analyzed by quant. cryomicroprobe NMR (qNMR) spectroscopy. The solns. from qNMR anal. were then used as stocks that were dild. into biochem. assays. Nine human phosphodiesterase-2 (PDE2) inhibitors yielded 36 new analogs. Products were tested for PDE2 inhibition, intrinsic clearance in human hepatocytes, and membrane permeability. Two of the products (2c and 4b) were 3-10× more potent than their resp. parent compds. and also had improved metabolic stability. Others offered insights into structure-activity relationships. Overall, this process of using liver microsomes at a submicromole scale of substrate is a useful approach to rapid and cost-effective late-stage lead diversification.
- 154Clouthier, C. M.; Pelletier, J. N. Expanding the organic toolbox: a guide to integrating biocatalysis in synthesis. Chem. Soc. Rev. 2012, 41, 1585– 1605, DOI: 10.1039/c2cs15286j[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsVajs78%253D&md5=a4ccf3d71518dd5dba80c21dc08c7ad4Expanding the organic toolbox. A guide to integrating biocatalysis in synthesisClouthier, Christopher M.; Pelletier, Joelle N.Chemical Society Reviews (2012), 41 (4), 1585-1605CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)A review. This crit. review presented an introduction to biocatalysis for synthetic chemists. Advances in biocatalysis of the past 5 years illustrate the breadth of applications for these powerful and selective catalysts in conducting key reaction steps. Asym. synthesis of value-added targets and other reaction types were covered, with an emphasis on pharmaceutical intermediates and bulk chems. Resources of interest for the non-initiated are provided, including specialized web-sites and service providers to facilitate identification of suitable biocatalysts, as well as refs. to recent vols. and reviews for more detailed biocatalytic procedures. Challenges related to the application of biocatalysts were discussed, including how green a biocatalytic reaction may be, and trends in biocatalyst improvement through enzyme engineering were presented (152 refs.).
- 155Segall, M. Advances in multiparameter optimization methods for de novo drug design. Expert Opin. Drug Discovery 2014, 9, 803– 817, DOI: 10.1517/17460441.2014.913565[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cnovFyltA%253D%253D&md5=a5cacbf56c2b849325259b8af9b6523bAdvances in multiparameter optimization methods for de novo drug designSegall MatthewExpert opinion on drug discovery (2014), 9 (7), 803-17 ISSN:.INTRODUCTION: A high-quality drug must achieve a balance of physicochemical and absorption, distribution, metabolism and elimination properties, safety and potency against its therapeutic target(s). Multiparameter optimization (MPO) methods guide the simultaneous optimization of multiple factors to quickly target compounds with the highest chance of downstream success. MPO can be combined with 'de novo design' methods to automatically generate and assess a large number of diverse structures and identify strategies to optimize a compound's overall balance of properties. AREAS COVERED: The article provides a review of MPO methods and recent developments in the methods and opinions in the field. It also provides a description of advances in de novo design that improve the relevance of automatically generated compound structures and integrate MPO. Finally, the article provides discussion of a recent case study of the automatic design of ligands to polypharmacological profiles. EXPERT OPINION: Recent developments have reduced the generation of chemically infeasible structures and improved the quality of compounds generated by de novo design methods. There are concerns about the ability of simple drug-like properties and ligand efficiency indices to effectively guide the detailed optimization of compounds. De novo design methods cannot identify a perfect compound for synthesis, but it can identify high-quality ideas for detailed consideration by an expert scientist.
- 156Segall, M. D.; Yusof, I.; Champness, E. J. Avoiding missed opportunities by analyzing the sensitivity of our decisions. J. Med. Chem. 2016, 59, 4267– 4277, DOI: 10.1021/acs.jmedchem.5b01921[ACS Full Text], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivFGmu7c%253D&md5=ee3d2630efd9eb85c1a576a9dc70bbffAvoiding Missed Opportunities by Analyzing the Sensitivity of Our DecisionsSegall, Matthew D.; Yusof, Iskander; Champness, Edmund J.Journal of Medicinal Chemistry (2016), 59 (9), 4267-4277CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Drug discovery is a multiparameter optimization process in which the goal of a project is to identify compds. that meet multiple property criteria required to achieve a therapeutic objective. However, once a profile of property criteria has been chosen, the impact of these criteria on the decisions made regarding progression of compds. or chem. series should be carefully considered. In some cases the decision is very sensitive to a specific property criterion, and such a criterion may artificially distort the direction of the project; any uncertainty in the "correct" value or the importance of this criterion may lead to valuable opportunities being missed. In this paper, we describe a method for analyzing the sensitivity of the prioritization of compds. to a multiparameter profile of property criteria. We show how the results can be easily interpreted and illustrate how this anal. can highlight new avenues for exploration.
- 157Shultz, M. D. Two decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 2019, 62, 1701, DOI: 10.1021/acs.jmedchem.8b00686[ACS Full Text], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslait73K&md5=d3c8b1107133dc0b7b277d22fa029597Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral DrugsShultz, Michael D.Journal of Medicinal Chemistry (2019), 62 (4), 1701-1714CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Two decades have passed since the rule of five ushered in the concept of "drug-like" properties. Attempts to quantify, correlate, and categorize mols. based on Ro5 parameters evolved into the introduction of efficiency metrics with far reaching consequences in decision making by industry leaders and scientists seeking to discover new medicines. Examn. of oral drug parameters approved before and after the original Ro5 anal. demonstrates that some parameters such as clogP and HBD remained const. while the cutoffs for parameters such as mol. wt. and HBA have increased substantially over the past 20 years. The time dependent increase in the mol. wt. of oral drugs during the past 20 years provides compelling evidence to disprove the hypothesis that mol. wt. is a "drug-like" property. This anal. does not validate parameters that have not changed as being "drug-like" but instead calls into question the entire hypothesis that "drug-like" properties exist.
- 158Doak, B. C.; Zheng, J.; Dobritzsch, D.; Kihlberg, J. How beyond rule of 5 drugs and clinical candidates bind to their targets. J. Med. Chem. 2016, 59, 2312– 2327, DOI: 10.1021/acs.jmedchem.5b01286[ACS Full Text], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhs1Cgu77F&md5=a417b605d1a3ffbc7ee84706401f01f4How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their TargetsDoak, Bradley C.; Zheng, Jie; Dobritzsch, Doreen; Kihlberg, JanJournal of Medicinal Chemistry (2016), 59 (6), 2312-2327CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To improve discovery of drugs for difficult targets, the opportunities of chem. space beyond the rule of 5 (bRo5) were examd. by retrospective anal. of a comprehensive set of structures for complexes between drugs and clin. candidates and their targets. The anal. illustrates the potential of compds. far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
- 159DeGoey, D. A.; Chen, H. J.; Cox, P. B.; Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 2018, 61, 2636– 2651, DOI: 10.1021/acs.jmedchem.7b00717[ACS Full Text], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFeitbjJ&md5=48984dc65410d83d4ac8ddaca030b024Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound CollectionDeGoey, David A.; Chen, Hui-Ju; Cox, Philip B.; Wendt, Michael D.Journal of Medicinal Chemistry (2018), 61 (7), 2636-2651CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncol. and virol. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chem. space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective anal. of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compds. and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclin. PK results with cLogD, no. of rotatable bonds, and no. of arom. rings.
- 160Raymer, B.; Bhattacharya, S. K. Lead-like drugs: A perspective. J. Med. Chem. 2018, 61, 10375, DOI: 10.1021/acs.jmedchem.8b00407[ACS Full Text], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtl2is73O&md5=e9fc17d69c7d671459fdaf77d6721829Lead-like Drugs: A PerspectiveRaymer, Brian; Bhattacharya, Samit K.Journal of Medicinal Chemistry (2018), 61 (23), 10375-10384CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Lead-like drugs, or drugs below mol. wt. 300, are an important and sometimes overlooked component of the current pharmacopeia and contemporary medicinal chem. practice. To examine the recent state-of-the-art in lead-like drug discovery, we surveyed recent drug approvals from 2011 to 2017 and top 200 prescribed medications, as well as provide case studies on recently approved lead-like drugs. Many of these recent drugs are close analogs of previously known drugs or natural substrates, with a key focus of their medicinal chem. optimization being the choice of a low mol. wt. starting point and maintaining low mol. wt. during the optimization. However, the identification of low mol. wt. starting points may be limited by the availability of suitable low mol. wt. screening sets. To increase the discovery rate of lead-like drugs, we suggest an increased focus on inclusion and prosecution of lead-like starting points in screening libraries.
- 161Johnson, T. W.; Gallego, R. A. Lipophilic efficiency as an important metric in drug design. J. Med. Chem. 2018, 61, 6401– 6420, DOI: 10.1021/acs.jmedchem.8b00077[ACS Full Text], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmsVahsbg%253D&md5=29f38880914fa75c33be3a640ace4309Lipophilic Efficiency as an Important Metric in Drug DesignJohnson, Ted W.; Gallego, Rebecca A.; Edwards, Martin P.Journal of Medicinal Chemistry (2018), 61 (15), 6401-6420CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Lipophilic efficiency (LipE) is an important metric that has been increasingly applied in drug discovery medicinal chem. lead optimization programs. In this perspective, using literature drug discovery examples, we discuss the concept of rigorously applying LipE to guide medicinal chem. lead optimization toward drug candidates with potential for superior in vivo efficacy and safety, esp. when guided by physiochem. property-based optimization (PPBO). Also highlighted are examples of small structural modifications such as addn. of single atoms, small functional groups, and cyclizations that produce large increases in LipE. Understanding the factors that may contribute to LipE changes through anal. of ligand-protein crystal structures and using structure-based drug design (SBDD) to increase LipE by design is also discussed. Herein we advocate for use of LipE anal. coupled with PPBO and SBDD as an efficient mechanism for drug design.
- 162Wager, T. T.; Kormos, B. L.; Brady, J. T.; Will, Y.; Aleo, M. D.; Stedman, D. B.; Kuhn, M.; Chandrasekaran, R. Y. Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies. J. Med. Chem. 2013, 56, 9771– 9779, DOI: 10.1021/jm401485p[ACS Full Text], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslOms7%252FL&md5=7efd1be4dbede3e4d3201154929bd641Improving the Odds of Success in Drug Discovery: Choosing the Best Compounds for in Vivo Toxicology StudiesWager, Travis T.; Kormos, Bethany L.; Brady, Joseph T.; Will, Yvonne; Aleo, Michael D.; Stedman, Donald B.; Kuhn, Max; Chandrasekaran, Ramalakshmi Y.Journal of Medicinal Chemistry (2013), 56 (23), 9771-9779CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A set of mols. that advanced into exploratory animal toxicol. studies (two species) was examd. to det. what properties contributed to success in these safety studies. Compds. were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicol. studies. The most predictive end point contributing to compd. survival was a predicted human efficacious concn. (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters.
- 163(a) Shultz, M. D.; Majumdar, D.; Chin, D. N.; Fortin, P. D.; Feng, Y.; Gould, T.; Kirby, C. A.; Stams, T.; Waters, N. J.; Shao, W. Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrases. J. Med. Chem. 2013, 56, 7049– 7059, DOI: 10.1021/jm400826j[ACS Full Text.], [CAS], Google Scholar163ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFCmu7%252FL&md5=b9174e9070c813b598cf15b261de9471Structure-efficiency relationship of [1,2,4]triazol-3-ylamines as novel nicotinamide isosteres that inhibit tankyrasesShultz, Michael D.; Majumdar, Dyuti; Chin, Donovan N.; Fortin, Pascal D.; Feng, Yun; Gould, Ty; Kirby, Christina A.; Stams, Travis; Waters, Nigel J.; Shao, WenlinJournal of Medicinal Chemistry (2013), 56 (17), 7049-7059CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tankyrases 1 and 2 are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that modulate Wnt pathway signaling. While amide- and lactam-based nicotinamide mimetics that inhibit tankyrase activity, such as XAV939, are well-known, the discovery and evaluation of a novel nicotinamide isostere that demonstrates selectivity over other PARP family members is reprted. The utilization of lipophilic efficiency-based structure-efficiency relationships (SER) to rapidly drive the evaluation of this series is demonstrated. These efforts led to a series of selective, cell-active compds. with soly., physicochem., and in vitro properties suitable for further optimization.(b) Shultz, M. D.; Cheung, A. K.; Kirby, C. A.; Firestone, B.; Fan, J.; Chen, C. H.; Chen, Z.; Chin, D. N.; Dipietro, L.; Fazal, A.; Feng, Y.; Fortin, P. D.; Gould, T.; Lagu, B.; Lei, H.; Lenoir, F.; Majumdar, D.; Ochala, E.; Palermo, M. G.; Pham, L.; Pu, M.; Smith, T.; Stams, T.; Tomlinson, R. C.; Toure, B. B.; Visser, M.; Wang, R. M.; Waters, N. J.; Shao, W. Identification of NVP-TNKS656: the use of structure-efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J. Med. Chem. 2013, 56, 6495– 6511, DOI: 10.1021/jm400807n[ACS Full Text], [CAS], Google Scholar163bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtV2msbfE&md5=db3f1a471ca757e0219a5175c5017e9bIdentification of NVP-TNKS656: The Use of Structure-Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase InhibitorShultz, Michael D.; Cheung, Atwood K.; Kirby, Christina A.; Firestone, Brant; Fan, Jianmei; Chen, Christine Hiu-Tung; Chen, Zhouliang; Chin, Donovan N.; DiPietro, Lucian; Fazal, Aleem; Feng, Yun; Fortin, Pascal D.; Gould, Ty; Lagu, Bharat; Lei, Huangshu; Lenoir, Francois; Majumdar, Dyuti; Ochala, Etienne; Palermo, M. G.; Pham, Ly; Pu, Minying; Smith, Troy; Stams, Travis; Tomlinson, Ronald C.; Toure, B. Barry; Visser, Michael; Wang, Run Ming; Waters, Nigel J.; Shao, WenlinJournal of Medicinal Chemistry (2013), 56 (16), 6495-6511CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodn. signature of binding, highly favorable physicochem. properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.
- 164Jiang, Z. Y.; Xu, L. L.; Lu, M. C.; Chen, Z. Y.; Yuan, Z. W.; Xu, X. L.; Guo, X. K.; Zhang, X. J.; Sun, H. P.; You, Q. D. Structure-activity and structure-property relationship and exploratory in vivo evaluation of the nanomolar Keap1-Nrf2 protein-protein interaction inhibitor. J. Med. Chem. 2015, 58, 6410– 6421, DOI: 10.1021/acs.jmedchem.5b00185[ACS Full Text], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXht12ksb7N&md5=458f0a612c34156a137759d99b741e3aStructure-Activity and Structure-Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1-Nrf2 Protein-Protein Interaction InhibitorJiang, Zheng-Yu; Xu, Li-Li; Lu, Meng-Chen; Chen, Zhi-Yun; Yuan, Zhen-Wei; Xu, Xiao-Li; Guo, Xiao-Ke; Zhang, Xiao-Jin; Sun, Hao-Peng; You, Qi-DongJournal of Medicinal Chemistry (2015), 58 (16), 6410-6421CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) is an effective way to activate Nrf2. Using the potent Keap1-Nrf2 PPI inhibitor that was reported by our group, we conducted a preliminary investigation of the structure-activity and structure-property relationships of the ring systems to improve the drug-like properties. Compd. 18e (I), which bore p-acetamido substituents on the side chain Ph rings, was the best choice for balancing PPI inhibition activity, physicochem. properties, and cellular Nrf2 activity. Cell-based expts. with 18e showed that the Keap1-Nrf2 PPI inhibitor can activate Nrf2 and induce the expression of Nrf2 downstream proteins in an Nrf2-dependent manner. An exploratory in vivo expt. was carried out to further evaluate the anti-inflammatory effects of 18e in a LPS-challenged mouse model. The primary results indicated that 18e could reduce the level of circulating pro-inflammatory cytokines induced by LPS and relieve the inflammatory response.
- 165(a) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. ACS Chem. Neurosci. 2010, 1, 435– 449, DOI: 10.1021/cn100008c[ACS Full Text.], [CAS], Google Scholar165ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjvVejtr8%253D&md5=e94998f65a420be6ee4dec4a987cb983Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike PropertiesWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.(b) Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem. Neurosci. 2016, 7, 767– 775, DOI: 10.1021/acschemneuro.6b00029[ACS Full Text.], [CAS], Google Scholar165bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksVSktbw%253D&md5=061c3aef6c88758cbaee1a2abb34796aCentral Nervous System Multiparameter Optimization Desirability: Application in Drug DiscoveryWager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, AnabellaACS Chemical Neuroscience (2016), 7 (6), 767-775CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Significant progress has been made in prospectively designing mols. using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the anal. reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochem. properties. The CNS MPO tool has helped to increase the percentage of compds. nominated for clin. development that exhibit alignment of ADME attributes, cross the blood-brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the no. of compds. submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicol. into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compds. nominated for clin. development.(c) Wager, T. T.; Chappie, T.; Horton, D.; Chandrasekaran, R. Y.; Samas, B.; Dunn-Sims, E. R.; Hsu, C.; Nawreen, N.; Vanase-Frawley, M. A.; O’Connor, R. E.; Schmidt, C. J.; Dlugolenski, K.; Stratman, N. C.; Majchrzak, M. J.; Kormos, B. L.; Nguyen, D. P.; Sawant-Basak, A.; Mead, A. N. Dopamine D3/D2 receptor antagonist PF-4363467 attenuates opioid drug-seeking behavior without concomitant D2 side effects. ACS Chem. Neurosci. 2017, 8, 165– 177, DOI: 10.1021/acschemneuro.6b00297[ACS Full Text], [CAS], Google Scholar165chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs1eltr7M&md5=abd6262987e08cb98b00d8057a52dc4fDopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side EffectsWager, Travis T.; Chappie, Thomas; Horton, David; Chandrasekaran, Ramalakshmi Y.; Samas, Brian; Dunn-Sims, Elizabeth R.; Hsu, Cathleen; Nawreen, Nawshaba; Vanase-Frawley, Michelle A.; O'Connor, Rebecca E.; Schmidt, Christopher J.; Dlugolenski, Keith; Stratman, Nancy C.; Majchrzak, Mark J.; Kormos, Bethany L.; Nguyen, David P.; Sawant-Basak, Aarti; Mead, Andy N.ACS Chemical Neuroscience (2017), 8 (1), 165-177CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)Dopamine receptor antagonism is a compelling mol. target for the treatment of a range of psychiatric disorders, including substance use disorders. From the authors' corporate compd. file the authors identified a structurally unique D3 receptor (D3R) antagonist scaffold, PNU-177864. Through a hybrid approach, the authors merged key pharmacophore elements from PNU-177864 and D3 agonist PF-592379 to yield the novel D3R/D2R antagonist PF-4363467. PF-4363467 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addn. to good physicochem. properties, PF-4363467 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.2 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R vs. other biogenic amine receptors. In vivo, PF-4363467 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not obsd. despite high D2 receptor occupancy (RO) in rodents, suggesting that compd. PF-4363467 has a unique in vivo profile. Collectively, the authors' data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.
- 166Vilums, M.; Zweemer, A. J.; Yu, Z.; de Vries, H.; Hillger, J. M.; Wapenaar, H.; Bollen, I. A.; Barmare, F.; Gross, R.; Clemens, J.; Krenitsky, P.; Brussee, J.; Stamos, D.; Saunders, J.; Heitman, L. H.; Ijzerman, A. P. Structure-kinetic relationships--an overlooked parameter in hit-to-lead optimization: a case of cyclopentylamines as chemokine receptor 2 antagonists. J. Med. Chem. 2013, 56, 7706– 7714, DOI: 10.1021/jm4011737[ACS Full Text], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVeksbvM&md5=9cd60706c51fa9d58b7674d069d21433Structure-Kinetic Relationships-An Overlooked Parameter in Hit-to-Lead Optimization: A Case of Cyclopentylamines as Chemokine Receptor 2 AntagonistsVilums, Maris; Zweemer, Annelien J. M.; Yu, Zhiyi; de Vries, Henk; Hillger, Julia M.; Wapenaar, Hannah; Bollen, Ilse A. E.; Barmare, Farhana; Gross, Raymond; Clemens, Jeremy; Krenitsky, Paul; Brussee, Johannes; Stamos, Dean; Saunders, John; Heitman, Laura H.; Ijzerman, Adriaan P.Journal of Medicinal Chemistry (2013), 56 (19), 7706-7714CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Preclin. models of inflammatory diseases (e.g., neuropathic pain, rheumatoid arthritis, and multiple sclerosis) have pointed to a crit. role of the chemokine receptor 2 (CCR2) and chemokine ligand 2 (CCL2). However, one of the biggest problems of high-affinity inhibitors of CCR2 is their lack of efficacy in clin. trials. We report a new approach for the design of high-affinity and long-residence-time CCR2 antagonists. We developed a new competition assocn. assay for CCR2, which allows us to investigate the relation of the structure of the ligand and its receptor residence time [i.e., structure-kinetic relationship (SKR)] next to a traditional structure-affinity relationship (SAR). By applying combined knowledge of SAR and SKR, we were able to re-evaluate the hit-to-lead process of cyclopentylamines as CCR2 antagonists. Affinity-based optimization yielded compd. 1 with good binding (Ki = 6.8 nM) but very short residence time (2.4 min). However, when the optimization was also based on residence time, the hit-to-lead process yielded compd. 22a, a new high-affinity CCR2 antagonist (3.6 nM), with a residence time of 135 min.
- 167Yu, Z.; van Veldhoven, J. P.; Louvel, J.; t Hart, I. M.; Rook, M. B.; van der Heyden, M. A.; Heitman, L. H.; IJzerman, A. P. Structure-affinity relationships (SARs) and Structure-kinetics relationships (SKRs) of Kv11.1 blockers. J. Med. Chem. 2015, 58, 5916– 5929, DOI: 10.1021/acs.jmedchem.5b00518[ACS Full Text], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtFSjsLvM&md5=22a7767e7f14a39a8eed2c0422d5156eStructure-Affinity Relationships (SARs) and Structure-Kinetics Relationships (SKRs) of Kv11.1 BlockersYu, Zhiyi; van Veldhoven, Jacobus P. D.; Louvel, Julien; 't Hart, Ingrid M. E.; Rook, Martin B.; van der Heyden, Marcel A. G.; Heitman, Laura H.; IJzerman, Adriaan P.Journal of Medicinal Chemistry (2015), 58 (15), 5916-5929CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and assocn. rates, there were hardly any variations in the dissocn. rate consts. of these mols. with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel mols., in particular in the pyridinium class of compds., to further address this peculiar phenomenon. We found mols. with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a kon-koff-KD kinetic map for all compds. and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of Kv11.1 blockers. Addnl., two representative compds. (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict Kv11.1-mediated cardiotoxicity.
- 168Rai, G.; Brimacombe, K. R.; Mott, B. T.; Urban, D. J.; Hu, X.; Yang, S. M.; Lee, T. D.; Cheff, D. M.; Kouznetsova, J.; Benavides, G. A.; Pohida, K.; Kuenstner, E. J.; Luci, D. K.; Lukacs, C. M.; Davies, D. R.; Dranow, D. M.; Zhu, H.; Sulikowski, G.; Moore, W. J.; Stott, G. M.; Flint, A. J.; Hall, M. D.; Darley-Usmar, V. M.; Neckers, L. M.; Dang, C. V.; Waterson, A. G.; Simeonov, A.; Jadhav, A.; Maloney, D. J. Discovery and optimization of potent, cell-active pyrazole-based inhibitors of lactate dehydrogenase (LDH). J. Med. Chem. 2017, 60, 9184– 9204, DOI: 10.1021/acs.jmedchem.7b00941[ACS Full Text], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslOkurfP&md5=a2df6432e54403e18abc6078fc30e692Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)Rai, Ganesha; Brimacombe, Kyle R.; Mott, Bryan T.; Urban, Daniel J.; Hu, Xin; Yang, Shyh-Ming; Lee, Tobie D.; Cheff, Dorian M.; Kouznetsova, Jennifer; Benavides, Gloria A.; Pohida, Katie; Kuenstner, Eric J.; Luci, Diane K.; Lukacs, Christine M.; Davies, Douglas R.; Dranow, David M.; Zhu, Hu; Sulikowski, Gary; Moore, William J.; Stott, Gordon M.; Flint, Andrew J.; Hall, Matthew D.; Darley-Usmar, Victor M.; Neckers, Leonard M.; Dang, Chi V.; Waterson, Alex G.; Simeonov, Anton; Jadhav, Ajit; Maloney, David J.Journal of Medicinal Chemistry (2017), 60 (22), 9184-9204CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The authors report the discovery and medicinal chem. optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quant. high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compds. with potent enzymic and cell-based inhibition of LDH enzymic activity. Lead compds. such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate prodn., and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compds. was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was detd. via SPR. Anal. of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metab. target.
- 169Brough, P. A.; Baker, L.; Bedford, S.; Brown, K.; Chavda, S.; Chell, V.; D’Alessandro, J.; Davies, N. G.; Davis, B.; Le Strat, L.; Macias, A. T.; Maddox, D.; Mahon, P. C.; Massey, A. J.; Matassova, N.; McKenna, S.; Meissner, J. W.; Moore, J. D.; Murray, J. B.; Northfield, C. J.; Parry, C.; Parsons, R.; Roughley, S. D.; Shaw, T.; Simmonite, H.; Stokes, S.; Surgenor, A.; Stefaniak, E.; Robertson, A.; Wang, Y.; Webb, P.; Whitehead, N.; Wood, M. Application of off-rate screening in the identification of novel pan-isoform inhibitors of pyruvate dehydrogenase kinase. J. Med. Chem. 2017, 60, 2271– 2286, DOI: 10.1021/acs.jmedchem.6b01478[ACS Full Text], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXis1agt7o%253D&md5=9727ca9e73096f63bbbb604c534155d8Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase KinaseBrough, Paul A.; Baker, Lisa; Bedford, Simon; Brown, Kirsten; Chavda, Seema; Chell, Victoria; D'Alessandro, Jalanie; Davies, Nicholas G. M.; Davis, Ben; Le Strat, Loic; Macias, Alba T.; Maddox, Daniel; Mahon, Patrick C.; Massey, Andrew J.; Matassova, Natalia; McKenna, Sean; Moore, Jonathan D.; Murray, James B.; Northfield, Christopher J.; Parry, Charles; Parsons, Rachel; Roughley, Stephen D.; Shaw, Terry; Simmonite, Heather; Stokes, Stephen; Surgenor, Allan; Stefaniak, Emma; Robertson, Alan; Wang, Yikang; Webb, Paul; Whitehead, Neil; Wood, MikeJournal of Medicinal Chemistry (2017), 60 (6), 2271-2286CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Libraries of non-purified resorcinol amide derivs. were screened by surface plasmon resonance (SPR) to det. the binding dissocn. const. (off-rate, kd) for compds. binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.
- 170Klebe, G. Applying thermodynamic profiling in lead finding and optimization. Nat. Rev. Drug Discovery 2015, 14, 95– 110, DOI: 10.1038/nrd4486[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVemtr4%253D&md5=c2e12760623de81335ce252cb804c602Applying thermodynamic profiling in lead finding and optimizationKlebe, GerhardNature Reviews Drug Discovery (2015), 14 (2), 95-110CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)Small-mol. drug discovery involves the optimization of various physicochem. properties of a ligand, particularly its binding affinity for its target receptor (or receptors). In recent years, there has been growing interest in using thermodn. profiling of ligand-receptor interactions in order to select and optimize those ligands that might be most likely to become drug candidates with desirable physicochem. properties. The thermodn. of binding is influenced by multiple factors, including hydrogen bonding and hydrophobic interactions, desolvation, residual mobility, dynamics and the local water structure. This article discusses key issues in understanding the effects of these factors and applying this knowledge in drug discovery.
- 171Cusack, K. P.; Wang, Y.; Hoemann, M. Z.; Marjanovic, J.; Heym, R. G.; Vasudevan, A. Design strategies to address kinetics of drug binding and residence time. Bioorg. Med. Chem. Lett. 2015, 25, 2019– 2027, DOI: 10.1016/j.bmcl.2015.02.027[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXktVCjsLg%253D&md5=c3735de36094915768dbecc7472917d4Design strategies to address kinetics of drug binding and residence timeCusack, Kevin P.; Wang, Ying; Hoemann, Michael Z.; Marjanovic, Jasmina; Heym, Roland G.; Vasudevan, AnilBioorganic & Medicinal Chemistry Letters (2015), 25 (10), 2019-2027CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A review. The kinetics of drug binding and drug residence time are recognized to be important in the clin. effectiveness of drug candidates. In most cases a long residence time of the drug-target complex results in an extended duration of pharmacodynamic activity, even when systemic concns. of drug have been notably reduced through elimination routes. Hence, if selective for target, long residence times can increase the duration of drug efficacy in vivo and can significantly diminish the potential for off-target-mediated toxicities. Furthermore, a compd. with a slower dissocn. rate may allow a reduced dosing schedule relative to a compd. with a rapid dissocn. rate. Factors contributing to long residence time that could be useful to medicinal chemists in the prospective design of compds. with long residence times will be discussed in this perspective. Particular emphasis will be on case studies highlighting how kinetics can be measured, modulated based on supporting structure kinetic relationships and whether these effects are translatable into man.
- 172Buch, I.; Giorgino, T.; De Fabritiis, G. Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulations. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 10184– 10189, DOI: 10.1073/pnas.1103547108[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXot1egu78%253D&md5=40fdd0ec62da71c0f11d57731ee518a1Complete reconstruction of an enzyme-inhibitor binding process by molecular dynamics simulationsBuch, Ignasi; Giorgino, Toni; De Fabritiis, GianniProceedings of the National Academy of Sciences of the United States of America (2011), 108 (25), 10184-10189, S10184/1-S10184/6CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)The understanding of protein-ligand binding is of crit. importance for biomedical research, yet the process itself has been very difficult to study because of its intrinsically dynamic character. Here, we have been able to quant. reconstruct the complete binding process of the enzyme-inhibitor complex trypsin-benzamidine by performing 495 mol. dynamics simulations of free ligand binding of 100 ns each, 187 of which produced binding events with an rmsd less than 2 Å compared to the crystal structure. The binding paths obtained are able to capture the kinetic pathway of the inhibitor diffusing from solvent (SO) to the bound (S4) state passing through two metastable intermediate states S2 and S3. Rather than directly entering the binding pocket the inhibitor appears to roll on the surface of the protein in its transition between S3 and the final binding pocket, whereas the transition between S2 and the bound pose requires rediffusion to S3. An estn. of the std. free energy of binding gives ΔG° = -5.2 0.4 kcal/mol (cf. the exptl. value -6.2 kcal/mol), and a two-states kinetic model kon = (1.5 ± 0.2) × 108 M-1 s-1 and koff = (9.5 ± 3.3) × 104 s-1 for unbound to bound transitions. The ability to reconstruct by simple diffusion the binding pathway of an enzyme-inhibitor binding process demonstrates the predictive power of unconventional high-throughput mol. simulations. Moreover, the methodol. is directly applicable to other mol. systems and thus of general interest in biomedical and pharmaceutical research.
- 173Perricone, U.; Gulotta, M. R.; Lombino, J.; Parrino, B.; Cascioferro, S.; Diana, P.; Cirrincione, G.; Padova, A. An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge. MedChemComm 2018, 9, 920– 936, DOI: 10.1039/C8MD00166A[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnvFemtrc%253D&md5=31f1de36caeaff89594e2b365052ea20An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challengePerricone, Ugo; Gulotta, Maria Rita; Lombino, Jessica; Parrino, Barbara; Cascioferro, Stella; Diana, Patrizia; Cirrincione, Girolamo; Padova, AlessandroMedChemComm (2018), 9 (6), 920-936CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Mol. dynamics (MD) has become increasingly popular due to the development of hardware and software solns. and the improvement in algorithms, which allowed researchers to scale up calcns. in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile anal. over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calcg. some kinetic and thermodn. parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimization of the mol. structure of a lead compd. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognized as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimize small mols. and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small mols. or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.
- 174Mollica, L.; Theret, I.; Antoine, M.; Perron-Sierra, F.; Charton, Y.; Fourquez, J. M.; Wierzbicki, M.; Boutin, J. A.; Ferry, G.; Decherchi, S.; Bottegoni, G.; Ducrot, P.; Cavalli, A. Molecular dynamics simulations and kinetic measurements to estimate and predict protein-ligand residence times. J. Med. Chem. 2016, 59, 7167– 7176, DOI: 10.1021/acs.jmedchem.6b00632[ACS Full Text], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFersrfE&md5=cbe23fde2bf0640f77501c0160821a68Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence TimesMollica, Luca; Theret, Isabelle; Antoine, Mathias; Perron-Sierra, Francoise; Charton, Yves; Fourquez, Jean-Marie; Wierzbicki, Michel; Boutin, Jean A.; Ferry, Gilles; Decherchi, Sergio; Bottegoni, Giovanni; Ducrot, Pierre; Cavalli, AndreaJournal of Medicinal Chemistry (2016), 59 (15), 7167-7176CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Exptl. approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force mol. dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodol. to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with exptl. kinetics measurements and X-ray crystallog., promptly checking the protocol's reliability by directly comparing computational predictions and exptl. measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estg. and predicting drug residence times.
- 175Krimmer, S. G.; Cramer, J.; Betz, M.; Fridh, V.; Karlsson, R.; Heine, A.; Klebe, G. Rational design of thermodynamic and kinetic binding profiles by optimizing surface water networks coating protein-bound ligands. J. Med. Chem. 2016, 59, 10530– 10548, DOI: 10.1021/acs.jmedchem.6b00998[ACS Full Text], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvVCjsL%252FN&md5=37092339ddcbe5a1ec6a10572b1a3213Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein-Bound LigandsKrimmer, Stefan G.; Cramer, Jonathan; Betz, Michael; Fridh, Veronica; Karlsson, Robert; Heine, Andreas; Klebe, GerhardJournal of Medicinal Chemistry (2016), 59 (23), 10530-10548CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S2' pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water mols. resulted in enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, the authors optimized the series by designing tailored P2' substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resoln. crystallog., microcalorimetry and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors.
- 176Nasief, N. N.; Tan, H.; Kong, J.; Hangauer, D. Water mediated ligand functional group cooperativity: the contribution of a methyl group to binding affinity is enhanced by a COO(−) group through changes in the structure and thermodynamics of the hydration waters of ligand-thermolysin complexes. J. Med. Chem. 2012, 55, 8283– 8302, DOI: 10.1021/jm300472k[ACS Full Text], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1SlsrjL&md5=8f77eb36b73bf36f914aa0de1d338ddeWater Mediated Ligand Functional Group Cooperativity: The Contribution of a Methyl Group to Binding Affinity is Enhanced by a COO- Group Through Changes in the Structure and Thermodynamics of the Hydration Waters of Ligand-Thermolysin ComplexesNasief, Nader N.; Tan, Hongwei; Kong, Jing; Hangauer, DavidJournal of Medicinal Chemistry (2012), 55 (19), 8283-8302CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ligand functional groups can modulate the contributions of one another to the ligand-protein binding thermodn., producing either pos. or neg. cooperativity. Data presented for four thermolysin phosphonamidate inhibitors demonstrate that the differential binding free energy and enthalpy caused by replacement of a H with a Me group, which binds in the well-hydrated S2' pocket, are more favorable in presence of a ligand carboxylate. The differential entropy is however less favorable. Dissection of these differential thermodn. parameters, X-ray crystallog., and d.-functional theory calcns. suggest that these cooperativities are caused by variations in the thermodn. of the complex hydration shell changes accompanying the H→Me replacement. Specifically, the COO- reduces both the enthalpic penalty and the entropic advantage of displacing water mols. from the S2' pocket and causes a subsequent acquisition of a more enthalpically, less entropically, favorable water network. This study contributes to understanding the important role water plays in ligand-protein binding.
- 177Liu, L. Efficient hit and lead compound evaluation strategy based on off-rate screening by surface plasmon resonance. J. Med. Chem. 2014, 57, 2843– 2844, DOI: 10.1021/jm5003815[ACS Full Text], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkslamu74%253D&md5=ed9a35d3ddf07415ad543bc7857f2243Efficient Hit and Lead Compound Evaluation Strategy Based on Off-Rate Screening by Surface Plasmon ResonanceLiu, LiuJournal of Medicinal Chemistry (2014), 57 (7), 2843-2844CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. The time-consuming and labor intensive compd. sepn. and purifn. process before they can be evaluated have been the bottleneck steps of novel drug discovery. A new screening strategy that can evaluate crude reaction mixts. without sepn. and purifn. by detg. dissocn. rate consts. of compds. in crude reaction mixts. was developed and validated by scientists from the Vernalis. This new strategy will significantly improve the efficiency of early stages in drug discovery.
- 178Murray, J. B.; Roughley, S. D.; Matassova, N.; Brough, P. A. Off-rate screening (ORS) by surface plasmon resonance. An efficient method to kinetically sample hit to lead chemical space from unpurified reaction products. J. Med. Chem. 2014, 57, 2845– 2850, DOI: 10.1021/jm401848a[ACS Full Text], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisVWguro%253D&md5=d3744f00df767e349024641e876e8100Off-Rate Screening (ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction ProductsMurray, James B.; Roughley, Stephen D.; Matassova, Natalia; Brough, Paul A.Journal of Medicinal Chemistry (2014), 57 (7), 2845-2850CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The dissocn. rate const. kd (off-rate) is the component of ligand-protein binding with the most significant potential to enhance compd. potency. Here we provide theor. and empirical data to show that this parameter can be detd. accurately from unpurified reaction products contg. designed test compds. This screening protocol is amenable to parallel chem., provides efficiencies of time and materials, and complements existing methodologies for the hit-to-lead phase in fragment-based drug discovery.
- 179Spagnuolo, L. A.; Eltschkner, S.; Yu, W.; Daryaee, F.; Davoodi, S.; Knudson, S. E.; Allen, E. K.; Merino, J.; Pschibul, A.; Moree, B.; Thivalapill, N.; Truglio, J. J.; Salafsky, J.; Slayden, R. A.; Kisker, C.; Tonge, P. J. Evaluating the contribution of transition-state destabilization to changes in the residence time of triazole-based InhA inhibitors. J. Am. Chem. Soc. 2017, 139, 3417– 3429, DOI: 10.1021/jacs.6b11148[ACS Full Text], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXitVeqs7g%253D&md5=46a5a148f16f540cb77889cf90a46d94Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA InhibitorsSpagnuolo, Lauren A.; Eltschkner, Sandra; Yu, Weixuan; Daryaee, Fereidoon; Davoodi, Shabnam; Knudson, Susan E.; Allen, Eleanor K. H.; Merino, Jonathan; Pschibul, Annica; Moree, Ben; Thivalapill, Neil; Truglio, James J.; Salafsky, Joshua; Slayden, Richard A.; Kisker, Caroline; Tonge, Peter J.Journal of the American Chemical Society (2017), 139 (9), 3417-3429CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A crit. goal of lead compd. selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodn. and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, the authors predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-contg. di-Ph ether with an increased residence time on InhA due to transition state destabilization rather than ground state stabilization. In the present work, the authors have evaluated the inhibition of InhA by 14 triazole-based di-Ph ethers and used a combination of enzyme kinetics and x-ray crystallog. to generate a structure-kinetic relationship (SKR) for time-dependent binding. The authors show that the triazole motif slows the rate of formation for the final drug-target complex by up to three orders of magnitude. In addn., the authors identify a novel inhibitor with a residence time on InhA of 220 min which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.
- 180Kokh, D. B.; Amaral, M.; Bomke, J.; Grädler, U.; Musil, D.; Buchstaller, H. P.; Dreyer, M. K.; Frech, M.; Lowinski, M.; Vallee, F.; Bianciotto, M.; Rak, A.; Wade, R. C. Estimation of drug-target residence times by τ-random acceleration molecular dynamics simulations. J. Chem. Theory Comput. 2018, 14, 3859– 3869, DOI: 10.1021/acs.jctc.8b00230[ACS Full Text], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpslWqt70%253D&md5=b2550dd6777bb7be3b63176c5e74fec5Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics SimulationsKokh, Daria B.; Amaral, Marta; Bomke, Joerg; Graedler, Ulrich; Musil, Djordje; Buchstaller, Hans-Peter; Dreyer, Matthias K.; Frech, Matthias; Lowinski, Maryse; Vallee, Francois; Bianciotto, Marc; Rak, Alexey; Wade, Rebecca C.Journal of Chemical Theory and Computation (2018), 14 (7), 3859-3869CODEN: JCTCCE; ISSN:1549-9618. (American Chemical Society)Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration mol. dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissocn. mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compds. and less than 2.0τ within congeneric series. Anal. of dissocn. trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.
- 181Cummins, D. J.; Bell, M. A. Integrating Everything: The molecule selection toolkit, a system for compound prioritization in drug discovery. J. Med. Chem. 2016, 59, 6999– 7010, DOI: 10.1021/acs.jmedchem.5b01338[ACS Full Text], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xjs12itbg%253D&md5=59b06f02ef4f2997eeff69bcf5f8ce59Integrating Everything: The Molecule Selection Toolkit, a System for Compound Prioritization in Drug DiscoveryCummins, David J.; Bell, Michael A.Journal of Medicinal Chemistry (2016), 59 (15), 6999-7010CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In recent years there have been numerous papers on the topic of multiattribute optimization in pharmaceutical discovery chem., applied to compd. prioritization. Many solns. proposed are static in nature; fixed functions are proposed for general purpose use. As needs change, these are modified and proposed as the latest enhancement. Rather than producing one more set of static functions, this work proposes a flexible approach to prioritizing compds. Most published approaches also lack a design component. This work describes a comprehensive implementation that includes predictive modeling, multiattribute optimization, and modern statistical design. This gives a complete package for effectively prioritizing compds. for lead generation and lead optimization. The approach described has been used at our company in various stages of discovery since 2001. An adaptable system alleviates the need for different static solns., each of which inevitably must be updated as the needs of a project change.
- 182McEnaney, P. J.; Parker, C. G.; Zhang, A. X.; Spiegel, D. A. Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease. ACS Chem. Biol. 2012, 7, 1139– 1151, DOI: 10.1021/cb300119g[ACS Full Text], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xpsl2isr0%253D&md5=17dcc667dae735c02b1f35a4cd6139c9Antibody-Recruiting Molecules: An Emerging Paradigm for Engaging Immune Function in Treating Human DiseaseMcEnaney, Patrick J.; Parker, Christopher G.; Zhang, Andrew X.; Spiegel, David A.ACS Chemical Biology (2012), 7 (7), 1139-1151CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)A review. Synthetic immunol., the development of synthetic systems capable of modulating and/or manipulating immunol. functions, represents an emerging field of research with manifold possibilities. One focus of this area has been to create low mol. wt. synthetic species, called antibody-recruiting mols. (ARMs), which are capable of enhancing antibody binding to disease-relevant cells or viruses, thus leading to their immune-mediated clearance. This article provides a thorough discussion of contributions in this area, beginning with the history of small-mol.-based technologies for modulating antibody recognition, followed by a systematic review of the various applications of ARM-based strategies. Thus, we describe ARMs capable of targeting cancer, bacteria, and viral pathogens, along with some of the scientific discoveries that have resulted from their development. Research in this area underscores the many exciting possibilities at the interface of org. chem. and immunobiol. and is positioned to advance both basic and clin. science in the years to come.
- 183Casi, G.; Neri, D. Antibody-drug conjugates and small molecule-drug conjugates: opportunities and challenges for the development of selective anticancer cytotoxic agents. J. Med. Chem. 2015, 58, 8751– 8761, DOI: 10.1021/acs.jmedchem.5b00457[ACS Full Text], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVagurzO&md5=24614e4825cbfe408e0b875db1826e68Antibody-Drug Conjugates and Small Molecule-Drug Conjugates: Opportunities and Challenges for the Development of Selective Anticancer Cytotoxic AgentsCasi, Giulio; Neri, DarioJournal of Medicinal Chemistry (2015), 58 (22), 8751-8761CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Conventional cancer chemotherapy heavily relies on the use of cytotoxic agents, which typically do not preferentially localize at the tumor site and cause toxicity to normal organs, preventing dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the neoplastic mass. For many years, the availability of ligands, capable of selective internalization into tumor cells, has been considered to be an essential requirement for the development of targeted cytotoxics. This assumption, however, has recently been challenged on the basis of therapeutic data obtained with noninternalizing drug conjugates. Moreover, quant. evaluations of the tumor targeting properties of antibodies and of small org. ligands have provided new insights for the implementation of optimal strategies for the development of targeted cytotoxics. In this article, we highlight opportunities and challenges assocd. with the clin. and industrial development of antibody-drug conjugates and small mol.-drug conjugates for cancer therapy.
- 184Murelli, R. P.; Zhang, A. X.; Michel, J.; Jorgensen, W. L.; Spiegel, D. A. Chemical control over immune recognition: a class of antibody-recruiting small molecules that target prostate cancer. J. Am. Chem. Soc. 2009, 131, 17090– 17092, DOI: 10.1021/ja906844e[ACS Full Text], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlKjsrvE&md5=1e6c183dc23acaa79b85c83835ceeb4fChemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules that Target Prostate CancerMurelli, Ryan P.; Zhang, Andrew X.; Michel, Julien; Jorgensen, William L.; Spiegel, David A.Journal of the American Chemical Society (2009), 131 (47), 17090-17092CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biol. evaluation of a class of bifunctional small mols. called antibody-recruiting mols. targeting prostate cancer (ARM-Ps) that enhance the recognition of prostate cancer cells by the human immune system. ARM-P derivs. were designed rationally via the computational anal. of crystallog. data, and we demonstrate here that these materials are able to (1) bind prostate-specific membrane antigen (PSMA) with high affinity (high pM to low nM), (2) template the formation of ternary complexes of anti-DNP antibodies, ARM-P, and LNCaP human prostate cancer cells, and (3) mediate the antibody-dependent killing of LNCaP cells in the presence of human effector cells. This manuscript describes the application of fundamental chem. principles to the design of a novel class of mols. with high therapeutic potential. We believe that this general small-mol.-based strategy could give rise to novel directions in treating cancer and other diseases.
- 185(a) Parker, C. G.; Domaoal, R. A.; Anderson, K. S.; Spiegel, D. A. An antibody-recruiting small molecule that targets HIV gp120. J. Am. Chem. Soc. 2009, 131, 16392– 16394, DOI: 10.1021/ja9057647[ACS Full Text.], [CAS], Google Scholar185ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXht1yjtLvN&md5=1c8913f7b4ac456ac7ccf2138f29fe0aAn Antibody-Recruiting Small Molecule That Targets HIV gp120Parker, Christopher G.; Domaoal, Robert A.; Anderson, Karen S.; Spiegel, David A.Journal of the American Chemical Society (2009), 131 (45), 16392-16394CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)HIV/AIDS is a global pandemic for which new treatment strategies are desperately needed. The authors have designed a novel small mol.I [X = (CH2CH2O)5, Y = = (CH2CH2O)3], designated as ARM-H, that has the potential to interfere with HIV survival through two mechanisms: (1) by recruiting antibodies to gp120-expressing virus particles and infected human cells, thus enhancing their uptake and destruction by the human immune system, and (2) by binding the viral glycoprotein gp120, inhibiting its interaction with the human protein CD4 and preventing virus entry. Here the authors demonstrate that ARM-H I is capable of simultaneously binding gp120, a component of the Env surface viral glycoprotein (found on the surface of both HIV and virus-infected cells) and anti-2,4-dinitrophenyl antibodies (already present in the human bloodstream). The ternary complex formed between the antibody, ARM-H I, and gp120 is immunol. active and leads to the complement-mediated destruction of Env-expressing cells. Furthermore, ARM-H prevents virus entry into human T-cells and should therefore be capable of inhibiting virus replication through two mutually reinforcing mechanisms (inhibition of virus entry and antibody-mediated killing). These studies demonstrate the viable anti-HIV activity of antibody-recruiting small mols. and have the potential to initiate novel paradigms in HIV treatment.(b) Parker, C. G.; Dahlgren, M. K.; Tao, R. N.; Li, D. T.; Douglass, E. F., Jr.; Shoda, T.; Jawanda, N.; Spasov, K. A.; Lee, S.; Zhou, N.; Domaoal, R. A.; Sutton, R. E.; Anderson, K. S.; Jorgensen, W. L.; Krystal, M.; Spiegel, D. A. Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules. Chem. Sci. 2014, 5, 2311– 2317, DOI: 10.1039/C4SC00484A[Crossref], [PubMed], [CAS], Google Scholar185bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnsFSqs7s%253D&md5=9ecc41d0ae77c6f0a5804d3b74127687Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting moleculesParker, Christopher G.; Dahlgren, Markus K.; Tao, Ran N.; Li, Don T.; Douglass, Eugene F.; Shoda, Takuji; Jawanda, Navneet; Spasov, Krasimir A.; Lee, Sangil; Zhou, Nannan; Domaoal, Robert A.; Sutton, Richard E.; Anderson, Karen S.; Krystal, Mark; Jorgensen, William L.; Spiegel, David A.Chemical Science (2014), 5 (6), 2311-2317CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Here we report on the structure-based optimization of antibody-recruiting mols. targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chem., biochem. and cellular assay anal., and computation. Our findings have afforded an optimized analog of ARM-H, which is ∼1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported deriv. Furthermore, computational anal., taken together with exptl. data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple distinct binding modes in interacting with gp120. These results are likely to prove enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.
- 186Genady, A. R.; Janzen, N.; Banevicius, L.; El-Gamal, M.; El-Zaria, M. E.; Valliant, J. F. Preparation and evaluation of radiolabeled antibody recruiting small molecules that target prostate-specific membrane antigen for combined radiotherapy and immunotherapy. J. Med. Chem. 2016, 59, 2660– 2673, DOI: 10.1021/acs.jmedchem.5b01881[ACS Full Text], [CAS], Google Scholar186https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XivVektL4%253D&md5=1fa1a23752e81b3732b9a8a6ffcdfc5ePreparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and ImmunotherapyGenady, Afaf R.; Janzen, Nancy; Banevicius, Laura; El-Gamal, Mahmoud; El-Zaria, Mohamed E.; Valliant, John F.Journal of Medicinal Chemistry (2016), 59 (6), 2660-2673CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The feasibility of developing a single agent that can deliver radioactive iodine and also direct cellular immune function by engaging endogenous antibodies as an antibody-recruiting small mol. (ARM) was detd. A library of new prostate-specific membrane antigen (PSMA)-binding ligands that contained antibody-recruiting 2,4-dinitrophenyl (DNP) groups and iodine were synthesized and screened in vitro and in vivo. A lead compd. (9b) showed high affinity for PSMA and the ability to bind anti-DNP antibodies. Biodistribution studies of the iodine-125 analog showed 3% ID/g in LNCaP xenograft tumors at 1 h postinjection with tumor-to-blood and tumor-to-muscle ratios of 10:1 and 44:1, resp. The radiolabeled analog was bound and internalized by LNCaP cells, with both functions blocked using a known PSMA inhibitor. A second candidate showed high tumor uptake (>10% ID/g) but had minimal binding to anti-DNP antibodies. The compds. reported represent the first examples of small mols. developed specifically for combination immunotherapy and radiotherapy for prostate cancer.
- 187Liu, Z.; Chen, X. Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy. Chem. Soc. Rev. 2016, 45, 1432– 1456, DOI: 10.1039/C5CS00158G[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XovVKkug%253D%253D&md5=6cbd8231b0f3dcdd776d464a835d535eSimple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapyLiu, Zhibo; Chen, XiaoyuanChemical Society Reviews (2016), 45 (5), 1432-1456CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-mol. wt. drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technol. (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chem. strategies of developing HSA binding mols. for coupling with drug mols. Moreover, we also concisely condense the recent progress of the most important clin. applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding.
- 188Matos, M. J. Learning from nature: the role of albumin in drug delivery. Future Med. Chem. 2018, 10, 983– 985, DOI: 10.4155/fmc-2018-0053[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt1GnsLw%253D&md5=5ba8158eaf7686844ac868f0bcff6c26Learning from nature: the role of albumin in drug deliveryMatos, Maria J.Future Medicinal Chemistry (2018), 10 (9), 983-985CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)Graphical Abstr. :.
- 189Kratz, F.; Muller-Driver, R.; Hofmann, I.; Drevs, J.; Unger, C. A novel macromolecular prodrug concept exploiting endogenous serum albumin as a drug carrier for cancer chemotherapy. J. Med. Chem. 2000, 43, 1253– 1256, DOI: 10.1021/jm9905864[ACS Full Text], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXhsFyhtLw%253D&md5=6a49fb71aa60db8d4fd949592fc8414eA Novel Macromolecular Prodrug Concept Exploiting Endogenous Serum Albumin as a Drug Carrier for Cancer ChemotherapyKratz, Felix; Mueller-Driver, Ralph; Hofmann, Inga; Drevs, Joachim; Unger, ClemensJournal of Medicinal Chemistry (2000), 43 (7), 1253-1256CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A maleimide phenylacetylhydrazone deriv. of doxorubicin (I) bound preferentially to endogenous serum albumin after incubation with human blood plasma or direct i.v. injection into mice. Preincubation studies with a maleimide compd. and coupling reactions with native serum albumin indicate that I binds to cytosine-34 of albumin which is an attractive binding site in blood plasma due to the fact that other major plasma proteins do not contain free HS groups. In addn., I showed a superior antitumor effect in an animal tumor model, i.e., murine renal cell carcinoma (RENCA), when compared to free doxorubicin at equitoxic dose. This increase in therapeutic efficacy can be best explained by an enhanced permeability of tumor blood vessels for circulating proteins and a subsequent retention due to lacking lymphatic recovery system in tumor tissue. Studies in the RENCA model have shown that renal cell carcinomas are highly vascularized indicating that circulating macromols. such as serum albumin and resp. conjugates might be trapped by the vascular network of these tumors. Although a more detailed anal. of the in situ coupling of thiol-binding drug derivs. to endogenous albumin is warranted, it is believed that the outlined macromol. prodrug strategy is an attractive approach of altering the pharmacokinetic profile of clin. established anticancer drugs and increasing their therapeutic index.
- 190Jafari, N.; Ahmed, R.; Gloyd, M.; Bloomfield, J.; Britz-McKibbin, P.; Melacini, G. Allosteric sensing of fatty acid binding by NMR: application to human serum albumin. J. Med. Chem. 2016, 59, 7457– 7465, DOI: 10.1021/acs.jmedchem.6b00410[ACS Full Text], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFyit7vN&md5=7ae3fd8dd89521b1a78b43d54f983087Allosteric Sensing of Fatty Acid Binding by NMR: Application to Human Serum AlbuminJafari, Naeimeh; Ahmed, Rashik; Gloyd, Melanie; Bloomfield, Jonathon; Britz-McKibbin, Philip; Melacini, GiuseppeJournal of Medicinal Chemistry (2016), 59 (16), 7457-7465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human serum albumin (HSA) serves not only as a physiol. oncotic pressure regulator and a ligand carrier but also as a biomarker for pathologies ranging from ischemia to diabetes. Moreover, HSA is a biopharmaceutical with a growing repertoire of putative clin. applications from hypovolemia to Alzheimer's disease. A key determinant of the physiol., diagnostic, and therapeutic functions of HSA is the amt. of long chain fatty acids (LCFAs) bound to HSA. Here, we propose to utilize 13C-oleic acid for the NMR-based assessment of albumin-bound LCFA concn. (CONFA). 13C-Oleic acid primes HSA for a LCFA-dependent allosteric transition that modulates the frequency sepn. between the two main 13C NMR peaks of HSA-bound oleic acid (ΔνAB). On the basis of ΔνAB, the overall [12C-LCFA]Tot/[HSA]Tot ratio is reproducibly estd. in a manner that is only minimally sensitive to glycation, albumin concn., or redox potential, unlike other methods to quantify HSA-bound LCFAs such as the albumin-cobalt binding assay.
- 191Shechter, Y.; Tsubery, H.; Fridkin, M. N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl](3)-gentamicin C(1) is a long-acting prodrug derivative. J. Med. Chem. 2002, 45, 4264– 4270, DOI: 10.1021/jm020042t[ACS Full Text], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XmtVylsr4%253D&md5=802cd413f5fe1112d4e5da8551fb6641N-[(2-Sulfo)-9-fluorenylmethoxycarbonyl]3-gentamicin C1 Is a Long-Acting Prodrug DerivativeShechter, Yoram; Tsubery, Haim; Fridkin, MatiJournal of Medicinal Chemistry (2002), 45 (19), 4264-4270CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Most low-mol.-wt. drugs are short-lived species in the circulatory system, being rapidly eliminated by glomerular filtration in the kidney. However, binding to human serum albumin (HSA) can slow clearance and prolong lifetime profile in vivo. In this study, we have engineered a gentamicin deriv. with affinity to albumin by linking three (2-sulfo)-9-fluorenylmethoxycarbonyl (FMS) to three amino groups of gentamicin C1. FMS3-gentamicin assocs. with HSA with a Ka value of (1.31 ± 0.2) × 105 M-1. It has less than 1% the antibacterial potency of native gentamicin. Upon incubation at pH 8.5 and 37 °C, the FMS moieties from FMS3-gentamicin undergo slow hydrolysis (t1/2 = 8.0 ± 0.2 h), leading to a linear regeneration of the antibacterial potency with a t1/2 value of 11 ± 0.7 h. FMS3-gentamicin is a long-lived species in the rat circulatory system. Following a single s.c. or i.v. administration, it maintains a prolonged pharmacokinetic profile with a peak and a "through" concn. of immuno/antibacterial active gentamicin exceeding 4-5 times the duration obtained by administered native gentamicin. To sum up, an approach aimed at elongating the lifetime of low-mol.-wt. drugs in vivo has been examd. here with gentamicin. Two to three FMS per mol of compd. are to be introduced to obtain an albumin assocg. affinity of Kd = 7.6-9.2 μM and, hence, to significantly extend the drug's lifetime in situ following administration. By use of this technol., the loss of pharmacol. potency with derivatization is of no consequence, since FMS moieties are hydrolyzed and activity is generated at physiol. conditions.
- 192Zheng, Y. R.; Suntharalingam, K.; Johnstone, T. C.; Yoo, H.; Lin, W.; Brooks, J. G.; Lippard, S. J. Pt(IV) prodrugs designed to bind non-covalently to human serum albumin for drug delivery. J. Am. Chem. Soc. 2014, 136, 8790– 8798, DOI: 10.1021/ja5038269[ACS Full Text], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXptl2itrs%253D&md5=541fe9e155e3f4e2f8d6f61f3d81ee5aPt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug DeliveryZheng, Yao-Rong; Suntharalingam, Kogularamanan; Johnstone, Timothy C.; Yoo, Hyunsuk; Lin, Wei; Brooks, Jamar G.; Lippard, Stephen J.Journal of the American Chemical Society (2014), 136 (24), 8790-8798CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Albumin is the most abundant protein in human serum and drugs that are administered i.v. inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asym. functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliph. tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analog bearing a fluorophore conjugated to the succinate ligand confirmed that these compds. are reduced by biol. reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphol. following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extn. with octanol completely removes the prodrug from an aq. soln. of HSA. Construct 7 is robust and can be isolated following fast protein liq. chromatog. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of redn. of the prodrug by ascorbate. The lead compd. from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.
- 193Bech, E. M.; Martos-Maldonado, M. C.; Wismann, P.; Sorensen, K. K.; van Witteloostuijn, S. B.; Thygesen, M. B.; Vrang, N.; Jelsing, J.; Pedersen, S. L.; Jensen, K. J. Peptide half-life extension: divalent, small-molecule albumin interactions direct the systemic properties of glucagon-like peptide 1 (GLP-1) analogues. J. Med. Chem. 2017, 60, 7434– 7446, DOI: 10.1021/acs.jmedchem.7b00787[ACS Full Text], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OmsLnO&md5=8ed415888afd85068ac6a4b98090b69cPeptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide 1 (GLP-1) AnaloguesBech, Esben M.; Maldonado, Manuel C.; Wismann, Pernille; Soerensen, Kasper K.; van Witteloostuijn, Soeren Blok; Thygesen, Mikkel B.; Vrang, Niels; Jelsing, Jacob; Pedersen, Soeren L.; Jensen, Knud J.Journal of Medicinal Chemistry (2017), 60 (17), 7434-7446CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Noncovalent binding of biopharmaceuticals to human serum albumin protects against enzymic degrdn. and renal clearance. Herein, we investigated the effect of mono- or divalent small-mol. albumin binders for half-life extension of peptides. For proof-of-principle, the clin. relevant glucagon-like peptide 1 (GLP-1) was functionalized with diflunisal, indomethacin, or both. In vitro, all GLP-1 analogs had subnanomolar GLP-1 receptor potency. Surface plasmon resonance revealed that both small mols. were able to confer albumin affinity to GLP-1 and indicated that affinity is increased for divalent analogs. In lean mice, the divalent GLP-1 analogs were superior to monovalent analogs with respect to control of glucose homeostasis and suppression of food intake. Importantly, divalent GLP-1 analogs showed efficacy comparable to liraglutide, an antidiabetic GLP-1 analog that carries a long-chain fatty acid. Finally, pharmacokinetic investigations of a divalent GLP-1 analog demonstrated a promising gain in circulatory half-life and absorption time compared to its monovalent equiv.
- 194Kratz, F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin. Invest. Drugs 2007, 16, 855– 866, DOI: 10.1517/13543784.16.6.855[Crossref], [PubMed], [CAS], Google Scholar194https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXltlOju7Y%253D&md5=88fec9cd817a4b10e54506d423eccd35DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trialsKratz, FelixExpert Opinion on Investigational Drugs (2007), 16 (6), 855-866CODEN: EOIDER; ISSN:1354-3784. (Informa Healthcare)A review. The (6-maleimidocaproyl)hydrazone deriv. of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that demonstrates superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats and dogs, including significantly reduced cardiotoxicity. After i.v. administration, DOXO-EMCH binds rapidly to the Cys-34 position of circulating albumin and accumulates in solid tumors due to passive targeting. In a clin. Phase I study, the dose of doxorubicin could be increased by a factor of 4.5-340 mg/m2 when 75 mg/m2 of free doxorubicin is considered to be the dose that can be administered as a single agent concomitant with the typical spectrum of side effects (i.e., myelotoxicity and mucositis). DOXO-EMCH was able to induce tumor regressions in anthracycline-sensitive tumors (i.e., breast cancer, small cell lung cancer and sarcoma). Phase II studies will be initiated at the beginning of 2007.
- 195Zhang, H.; Wang, K.; Na, K.; Li, D.; Li, Z.; Zhao, D.; Zhong, L.; Wang, M.; Kou, L.; Luo, C.; Zhang, H.; Kan, Q.; Ding, H.; He, Z.; Sun, J. Striking a balance between carbonate/carbamate linkage bond- and reduction-sensitive disulfide bond-bearing linker for tailored controlled release: in situ covalent-albumin-binding gemcitabine prodrugs promote bioavailability and tumor accumulation. J. Med. Chem. 2018, 61, 4904– 4917, DOI: 10.1021/acs.jmedchem.8b00293[ACS Full Text], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXps12ls7w%253D&md5=961b64121072b0f201faa7aa6854c933Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor AccumulationZhang, Huicong; Wang, Kuanglei; Na, Kexin; Li, Dan; Li, Zhenbao; Zhao, Dongyang; Zhong, Lu; Wang, Menglin; Kou, Longfa; Luo, Cong; Zhang, Haotian; Kan, Qiming; Ding, Huaiwei; He, Zhonggui; Sun, JinJournal of Medicinal Chemistry (2018), 61 (11), 4904-4917CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromol. prodrugs after i.v. administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, resp.), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, esp. the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.
- 197Chong, H.; Yao, X.; Zhang, C.; Cai, L.; Cui, S.; Wang, Y.; He, Y. Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitor. PLoS One 2012, 7, e32599, DOI: 10.1371/journal.pone.0032599[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjvFaisLs%253D&md5=e56929dcfffbd80e1e1c1f333fb38934Biophysical property and broad anti-HIV activity of albuvirtide, a 3-maleimimidopropionic acid-modified peptide fusion inhibitorChong, Huihui; Yao, Xue; Zhang, Chao; Cai, Lifeng; Cui, Sheng; Wang, Youchun; He, YuxianPLoS One (2012), 7 (3), e32599CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Albuvirtide (ABT) is a 3-maleimimidopropionic acid (MPA)-modified peptide HIV fusion inhibitor that can irreversibly conjugate to serum albumin. Previous studies demonstrated its in vivo long half-life and potent anti-HIV activity. Here, we focused to characterize its biophys. properties and evaluate its antiviral spectrum. In contrast to T20 (Enfuvirtide, Fuzeon), ABT was able to form a stable α-helical conformation with the target sequence and block the fusion-active six-helix bundle (6-HB) formation in a dominant-neg. manner. It efficiently inhibited HIV-1 Env-mediated cell membrane fusion and virus entry. A large panel of 42 HIV-1 pseudoviruses with different genotypes were constructed and used for the antiviral evaluation. The results showed that ABT had potent inhibitory activity against the subtypes A, B and C that predominate the worldwide AIDS epidemics, and subtype B', CRF07_BC and CRF01_AE recombinants that are currently circulating in China. Furthermore, ABT was also highly effective against HIV-1 variants resistant to T20. Taken together, our data indicate that the chem. modified peptide ABT can serve as an ideal HIV-1 fusion inhibitor.
- 198(a) Bohn, P.; Le Fur, N.; Hagues, G.; Costentin, J.; Torquet, N.; Papamicaël, C.; Marsais, F.; Levacher, V. Rational design of central selective acetylcholinesterase inhibitors by means of a ″bio-oxidisable prodrug″ strategy. Org. Biomol. Chem. 2009, 7, 2612– 2618, DOI: 10.1039/b903041g[Crossref], [PubMed], [CAS], Google Scholar.198ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXnvV2nsLk%253D&md5=5a873be253275a9b0d93b4da8c56439aRational design of central selective acetylcholinesterase inhibitors by means of a "bio-oxidisable prodrug" strategyBohn, Pierre; Le Fur, Nicolas; Hagues, Guillaume; Costentin, Jean; Torquet, Nicolas; Papamicael, Cyril; Marsais, Francis; Levacher, VincentOrganic & Biomolecular Chemistry (2009), 7 (12), 2612-2618CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)This work deals with the design of a "bio-oxidizable prodrug" strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects obsd. with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogs of rivastigmine. The key activation step of the prodrug involves an oxidn. of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the pos. charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biol. evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 106 nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 μM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogs of rivastigmine in quinoline series as appealing chem. tools for further in vivo development of this "bio-oxidizable prodrug" approach.(b) Bohn, P.; Gourand, F.; Papamicaël, C.; Ibazizène, M.; Dhilly, M.; Gembus, V.; Alix, F.; Ţînţaş, M. L.; Marsais, F.; Barré, L.; Levacher, V. Dihydroquinoline carbamate derivatives as ″bio-oxidizable″ prodrugs for brain delivery of acetylcholinesterase inhibitors: [11C] Radiosynthesis and biological evaluation. ACS Chem. Neurosci. 2015, 6, 737– 744, DOI: 10.1021/cn5003539[ACS Full Text.], [CAS], Google Scholar198bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXivFGks7k%253D&md5=e089ec639e23d630f228ac0b33090ed8Dihydroquinoline Carbamate Derivatives as "Bio-oxidizable" Prodrugs for Brain Delivery of Acetylcholinesterase Inhibitors: [11C] Radiosynthesis and Biological EvaluationBohn, Pierre; Gourand, Fabienne; Papamicael, Cyril; Ibazizene, Meziane; Dhilly, Martine; Gembus, Vincent; Alix, Florent; Tintas, Mihaela-Liliana; Marsais, Francis; Barre, Louisa; Levacher, VincentACS Chemical Neuroscience (2015), 6 (5), 737-744CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)With the aim of improving the efficiency of marketed acetylcholinesterase (AChE) inhibitors in the symptomatic treatment of Alzheimer's disease, plagued by adverse effects arising from peripheral cholinergic activation, this work reports a biol. evaluation of new central AChE inhibitors based on an original "bio-oxidizable" prodrug strategy. After peripheral injection of the prodrug I [IC50 > 1 mM (hAChE)] in mice, monitoring markers of central and peripheral cholinergic activation provided in vivo proof-of-concept for brain delivery of the drug II [IC50 = 20 nM (hAChE)] through central redox activation of I. Interestingly, peripheral cholinergic activation has been shown to be limited in time, likely due to the presence of a permanent pos. charge in II promoting rapid elimination of the AChE inhibitor from the circulation of mice. To support these assumptions, the radiosynthesis with carbon-11 of prodrug I was developed for addnl. ex vivo studies in rats. Whole-body biodistribution of radioactivity revealed high accumulation in excretory organs along with moderate but rapid brain uptake. Radio-HPLC analyses of brain samples confirm rapid CNS penetration of [11C]-I, while identification of [11C]-II and [11C]-III both accounts for central redox activation of I and pseudoirreversible inhibition of AChE, resp. Finally, Caco-2 permeability assays predicted metabolite III as a substrate for efflux transporters (P-gp interalia), suggesting that metabolite III might possibly be actively transported out of the brain. Overall, a large body of evidence from in vivo and ex vivo studies on small animals has been collected to validate this "bio-oxidizable" prodrug approach, emerging as a very promising strategy in the rational design of selective central AChE inhibitors.(c) Peauger, L.; Azzouz, R.; Gembus, V.; Ţînţaş, M. L.; Sopková-de Oliveira Santos, J.; Bohn, P.; Papamicaël, C.; Levacher, V. Donepezil-based central acetylcholinesterase inhibitors by means of a ″bio-oxidizable″ prodrug strategy: design, synthesis, and in vitro biological evaluation. J. Med. Chem. 2017, 60, 5909– 5926, DOI: 10.1021/acs.jmedchem.7b00702[ACS Full Text.], [CAS], Google Scholar198chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpvFeju74%253D&md5=bd539cf43f39c5058b243fb1bbdb4da4Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a "Bio-Oxidizable" Prodrug Strategy: Design, Synthesis, and in Vitro Biological EvaluationPeauger, Ludovic; Azzouz, Rabah; Gembus, Vincent; Tintas, Mihaela-Liliana; Sopkova-de Oliveira Santos, Jana; Bohn, Pierre; Papamicael, Cyril; Levacher, VincentJournal of Medicinal Chemistry (2017), 60 (13), 5909-5926CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the std. drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compds. 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biol. expts.(d) Azzouz, R.; Peauger, L.; Gembus, V.; Ţînţaş, M. L.; Sopková-de Oliveira Santos, J.; Papamicaël, C.; Levacher, V. Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine ″bio-oxidizable″ prodrugs: Synthesis, biological evaluation and structure-activity relationship. Eur. J. Med. Chem. 2018, 145, 165– 190, DOI: 10.1016/j.ejmech.2017.12.084[Crossref], [PubMed], [CAS], Google Scholar198dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltlOrtg%253D%253D&md5=bd793423976324f61980466d8c0a4c68Novel donepezil-like N-benzylpyridinium salt derivatives as AChE inhibitors and their corresponding dihydropyridine "bio-oxidizable" prodrugs: Synthesis, biological evaluation and structure-activity relationshipAzzouz, Rabah; Peauger, Ludovic; Gembus, Vincent; Tintas, Mihaela-Liliana; Sopkova-de Oliveira Santos, Jana; Papamicael, Cyril; Levacher, VincentEuropean Journal of Medicinal Chemistry (2018), 145 (), 165-190CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A total of fifty one N-benzylpyridinium quaternary donepezil analogs B1-3 I [R = Ph, 2,3-dihydro-1,3-benzoxazol-2-yl, cyclohexyl, etc.; R1 = H, F, OH, OCH3; R2 = H, OCH3; R1, R2 = -OCH2O-; EWG = H, CN, CF3, C(O)NH2, etc.; X = Br, I; n = 0, 1, 2] and twenty two prodrugs A1-3 II was synthesized and evaluated for their inhibitory activities against hAChE and eqBuChE. While most prodrugs A1-3 were demonstrated to be inactive against AChE (IC50 >10 μM), a large no. of the corresponding N-benzylpyridinium salt B1-3 exhibited appealing three-to-one-digit nanomolar hAChE inhibitory activities and even reaching subnanomolar activity (IC50 = 0.36 nM). In addn., in silico docking studies were conducted for several compds. to explain the more relevant in vitro results. Lastly, the influence of the two stereogenic centers in prodrugs A was also evaluated, highlighting not only marked differences in residual AChE inhibitory activity of the four sepd. isomers of prodrug II [R = 3-chlorophenyl; R1 = H, F, OH, OCH3; R2 = OCH3; EWG = C(O)NH2;n = 1] (IC50 ranging from 173 nM to 10 μM) but also significant variations of the oxidn. rate between two sepd. diastereoisomers of prodrug II [R = phenyl; R1 = R2 = OCH3; EWG = C(O)CH3; n = 2]. This work provides useful information in the search of a preclin. candidate to conduct further development of this attractive "bio-oxidizable" prodrug strategy.
- 199Childress, E. S.; Alexopoulos, S. J.; Hoehn, K. L.; Santos, W. L. Small molecule mitochondrial uncouplers and their therapeutic potential. J. Med. Chem. 2018, 61, 4641– 4655, DOI: 10.1021/acs.jmedchem.7b01182[ACS Full Text], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVCks77F&md5=bef89f85633a157c8dadeaa0d0114403Small Molecule Mitochondrial Uncouplers and Their Therapeutic PotentialChildress, Elizabeth S.; Alexopoulos, Stephanie J.; Hoehn, Kyle L.; Santos, Webster L.Journal of Medicinal Chemistry (2018), 61 (11), 4641-4655CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Small mol. mitochondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metab. from ATP generation. The therapeutic potential of mitochondrial uncouplers has been investigated for the treatment of metabolic diseases such as obesity and type 2 diabetes (T2D), ischemia-reperfusion injury, and neurodegenerative diseases. This communication will review the small mol. mitochondrial uncouplers reported to date and explore their potential as therapeutics.
- 200Millard, M.; Gallagher, J. D.; Olenyuk, B. Z.; Neamati, N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J. Med. Chem. 2013, 56, 9170– 9179, DOI: 10.1021/jm4012438[ACS Full Text], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1KktLvI&md5=433d093d02a482a570ea77e3b32629a3A Selective Mitochondrial-Targeted Chlorambucil with Remarkable Cytotoxicity in Breast and Pancreatic CancersMillard, Melissa; Gallagher, John D.; Olenyuk, Bogdan Z.; Neamati, NouriJournal of Medicinal Chemistry (2013), 56 (22), 9170-9179CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, the authors describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium deriv. of the nitrogen mustard chlorambucil. The authors show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of re-purposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.
- 201(a) Ye, Y.; Zhang, T.; Yuan, H.; Li, D.; Lou, H.; Fan, P. Mitochondria-targeted lupane triterpenoid derivatives and their selective apoptosis-inducing anticancer mechanisms. J. Med. Chem. 2017, 60, 6353– 6363, DOI: 10.1021/acs.jmedchem.7b00679[ACS Full Text.], [CAS], Google Scholar201ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtV2qsr3E&md5=b1461bf97acb75e7c68e976462804065Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer MechanismsYe, Yaqing; Zhang, Tao; Yuan, Huiqing; Li, Defeng; Lou, Hongxiang; Fan, PeihongJournal of Medicinal Chemistry (2017), 60 (14), 6353-6363CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Betulin and betulinic acid have been widely studied for their anticancer activities. However, their further development is limited due to low bioavailability, poor aq. soly., and limited intracellular accumulation. In the present study, a triphenylphosphonium cation moiety was linked to betulin and betulinic acid to specifically target them to cancer cell mitochondria. Biol. characterization established that uptake of mitochondria-targeted compd. 1a in the mitochondria of cancer cells was increased compared to betulin. The mitochondria-targeted derivs. of betulin and betulinic acid showed stronger cytotoxicity than their parent drugs and exhibited more cytotoxic effects in cancer cells than normal cells. The mechanisms may involve the mitochondrial apoptotic pathway, probably caused by the induction of reactive oxygen species prodn. and reducing mitochondrial membrane potential. More importantly, 1a significantly inhibited cancer cell proliferation and migration in an in vivo zebrafish xenograft model. Collectively, these results encourage further study of 1a analogs as anticancer agents.(b) Chang, W.; Liu, J.; Zhang, M.; Shi, H.; Zheng, S.; Jin, X.; Gao, Y.; Wang, S.; Ji, A.; Lou, H. Efflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cation. Nat. Commun. 2018, 9, 5102, DOI: 10.1038/s41467-018-07633-9[Crossref], [PubMed], [CAS], Google Scholar201bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crns1aisQ%253D%253D&md5=430b9cf5f0a46c304c8e7b2e7afd089eEfflux pump-mediated resistance to antifungal compounds can be prevented by conjugation with triphenylphosphonium cationChang Wenqiang; Liu Jun; Zhang Ming; Shi Hongzhuo; Zheng Sha; Jin Xueyang; Gao Yanhui; Wang Shuqi; Ji Aiguo; Lou HongxiangNature communications (2018), 9 (1), 5102 ISSN:.Antifungal resistance due to upregulation of efflux pumps is prevalent in clinical Candida isolates. Potential efflux pump substrates (PEPSs), which are active against strains deficient in efflux pumps but inactive against wild-type strains, are usually missed in routine antifungal screening. Here we present a method for identification of PEPSs, and show that conjugation with mitochondria-targeting triphenylphosphonium cation (TPP(+)) can enhance or restore the compounds' antifungal activity. The screening method involves co-culturing a wild-type C. albicans strain and a Cdr efflux pump-deficient strain, labelled with different fluorescent proteins. We identify several PEPSs from a library of natural terpenes, and restore their antifungal activity against wild-type and azole-resistant C. albicans by conjugation with TPP(+). The most active conjugate (IS-2-Pi-TPP) kills C. albicans cells, prevents biofilm formation and eliminates preformed biofilms, without inducing significant resistance. The antifungal activity is accompanied by mitochondrial dysfunction and increased levels of intracellular reactive oxygen species. In addition, IS-2-Pi-TPP is effective against C. albicans in a mouse model of skin infection.
- 202Bauer, R. A. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discovery Today 2015, 20, 1061– 1073, DOI: 10.1016/j.drudis.2015.05.005[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXptlOnu7s%253D&md5=6ba5b016d2804c7d56838a2724b9a0b9Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapiesBauer, Renato A.Drug Discovery Today (2015), 20 (9), 1061-1073CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)Drugs that covalently bond to their biol. targets have a long history in drug discovery. A look at drug approvals in recent years suggests that covalent drugs will continue to make impacts on human health for years to come. Although fraught with concerns about toxicity, the high potencies and prolonged effects achievable with covalent drugs may result in less-frequent drug dosing and in wide therapeutic margins for patients. Covalent inhibition can also dissoc. drug pharmacodynamics (PD) from pharmacokinetics (PK), which can result in desired drug efficacy for inhibitors that have short systemic exposure. Evidence suggests that there is a reduced risk for the development of resistance against covalent drugs, which is a major challenge in areas such as oncol. and infectious disease.
- 203Zhao, Z.; Liu, Q.; Bliven, S.; Xie, L.; Bourne, P. E. Determining cysteines available for covalent inhibition across the human kinome. J. Med. Chem. 2017, 60, 2879– 2889, DOI: 10.1021/acs.jmedchem.6b01815[ACS Full Text], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVGjsLg%253D&md5=22ea95ce38eb0836d32c1332dba54fadDetermining Cysteines Available for Covalent Inhibition Across the Human KinomeZhao, Zheng; Liu, Qingsong; Bliven, Spencer; Xie, Lei; Bourne, Philip E.Journal of Medicinal Chemistry (2017), 60 (7), 2879-2889CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Covalently bound protein kinase inhibitors have been frequently designed to target non-catalytic Cys residues at the ATP binding site. Thus, it is important to know if a given Cys residue can form a covalent bond. Here, we combined a function-site interaction fingerprint method and DFT calcns. to det. the potential of Cys residues to form a covalent interaction with an inhibitor. By harnessing the human structural kinome, a comprehensive structure-based binding site Cys dataset was assembled. The orientation of the Cys SH group indicated which Cys residues could potentially form covalent bonds. These covalent inhibitor accessible Cys residues were located within 5 kinase regions (P-loop, roof of pocket, front pocket, catalytic-2 of the catalytic loop and DFG-3 close to the DFG peptide). In an independent test set, these Cys residues covered 95% of covalent kinase inhibitors. Thus, this study provides new insights into Cys reactivity and preference which is important for the prospective development of covalent kinase inhibitors.
- 204Akbar, A.; McNeil, N. M. R.; Albert, M. R.; Ta, V.; Adhikary, G.; Bourgeois, K.; Eckert, R. L.; Keillor, J. W. Structure-activity relationships of potent, targeted covalent inhibitors that abolish both the transamidation and GTP binding activities of human tissue transglutaminase. J. Med. Chem. 2017, 60, 7910– 7927, DOI: 10.1021/acs.jmedchem.7b01070[ACS Full Text], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsVejsrfL&md5=428ab48c5dd22fb85f14d0bdd21f7ab5Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue TransglutaminaseAkbar, Abdullah; McNeil, Nicole M. R.; Albert, Marie R.; Ta, Viviane; Adhikary, Gautam; Bourgeois, Karine; Eckert, Richard L.; Keillor, Jeffrey W.Journal of Medicinal Chemistry (2017), 60 (18), 7910-7927CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been assocd. with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, the authors present a series of targeted covalent inhibitors (TCIs) based on the previously reported Cbz-Lys scaffold. From this structure-activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (kinact/KI > 105 M-1 min-1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 μM, representing a significant improvement over the previously reported "hit" NC9.
- 205Muth, F.; El-Gokha, A.; Ansideri, F.; Eitel, M.; Doring, E.; Sievers-Engler, A.; Lange, A.; Boeckler, F. M.; Lammerhofer, M.; Koch, P.; Laufer, S. A. Tri- and tetrasubstituted pyridinylimidazoles as covalent inhibitors of c-Jun N-terminal kinase 3. J. Med. Chem. 2017, 60, 594– 607, DOI: 10.1021/acs.jmedchem.6b01180[ACS Full Text], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitV2nu7zI&md5=fbcdb576a6f2a2cbb30d35bcf7e9d062Tri- and Tetrasubstituted Pyridinylimidazoles as Covalent Inhibitors of c-Jun N-Terminal Kinase 3Muth, Felix; El-Gokha, Ahmed; Ansideri, Francesco; Eitel, Michael; Doering, Eva; Sievers-Engler, Adrian; Lange, Andreas; Boeckler, Frank M.; Laemmerhofer, Michael; Koch, Pierre; Laufer, Stefan A.Journal of Medicinal Chemistry (2017), 60 (2), 594-607CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The concept of covalent inhibition of c-Jun N-terminal kinase 3 (JNK3) was successfully transferred to the well validated pyridinylimidazole scaffolds varying several structural features in order to deduce crucial structure-activity relationships. Joint targeting of the hydrophobic region I and methylation of imidazole-N1 position increased the activity and reduced the no. of off-targets. The most promising covalent inhibitor, 3-acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide [2079881-38-0], inhibits the JNK3 in the sub-nanomolar range (IC50 = 0.3 nM), shows high metabolic stability in human liver microsomes and displays excellent selectivity in a screen against 410 kinases. Covalent binding to Cys-154 of the enzyme was confirmed by incubation of the inhibitors with wild-type JNK3 and JNK3-C154A mutant followed by mass spectrometry.
- 206Shi, L.; Zhong, Z.; Li, X.; Zhou, Y.; Pan, Z. Discovery of an orally available janus kinase 3 selective covalent inhibitor. J. Med. Chem. 2019, 62, 1054, DOI: 10.1021/acs.jmedchem.8b01823[ACS Full Text], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjs1Ghug%253D%253D&md5=17792310c69501e5a645a63b79aa4826Discovery of an Orally Available Janus Kinase 3 Selective Covalent InhibitorShi, Liyang; Zhong, Zhenpeng; Li, Xitao; Zhou, Yiqing; Pan, ZhengyingJournal of Medicinal Chemistry (2019), 62 (2), 1054-1066CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3's strong binding preference to ATP (ATP), a no. of inhibitors exhibit large gaps between enzymic and cellular potency, which hampers efforts to dissect the roles of JAK3 in cellular settings. Using a targeted covalent inhibitor approach, we discovered compd. 32, which overcame ATP competition (1 mM) in the enzymic assay, and demonstrated significantly improved inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and human peripheral blood mononuclear cells. Compd. 32 also exhibited high selectivity within the JAK family and good pharmacokinetic properties. Thus, it may serve as a highly valuable tool mol. to study the overlapping roles of JAK family kinases in complex biol. settings. Our study also suggested that for covalent kinase inhibitors, esp. those targeting kinases with low Km ATP values, the reversible interactions between mols. and proteins should be carefully optimized to improve the overall potency.
- 207(a) Patricelli, M. P.; Janes, M. R.; Li, L. S.; Hansen, R.; Peters, U.; Kessler, L. V.; Chen, Y.; Kucharski, J. M.; Feng, J.; Ely, T.; Chen, J. H.; Firdaus, S. J.; Babbar, A.; Ren, P.; Liu, Y. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discovery 2016, 6, 316– 329, DOI: 10.1158/2159-8290.CD-15-1105[Crossref], [PubMed], [CAS], Google Scholar.207ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XktVyru7s%253D&md5=41db2f02006e8f0be7a9bb47354addcdSelective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive StatePatricelli, Matthew P.; Janes, Matthew R.; Li, Lian-Sheng; Hansen, Rasmus; Peters, Ulf; Kessler, Linda V.; Chen, Yuching; Kucharski, Jeff M.; Feng, Jun; Ely, Tess; Chen, Jeffrey H.; Firdaus, Sarah J.; Babbar, Anjali; Ren, Pingda; Liu, YiCancer Discovery (2016), 6 (3), 316-329CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)KRAS gain-of-function mutations occur in approx. 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRASG12C that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition obsd. for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRASG12C is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRASG12C mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. Significance: A cell-active, mutant-specific, covalent inhibitor of KRASG12C is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compd., we demonstrate that KRASG12C oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state.(b) Hansen, R.; Peters, U.; Babbar, A.; Chen, Y.; Feng, J.; Janes, M. R.; Li, L. S.; Ren, P.; Liu, Y.; Zarrinkar, P. P. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat. Struct. Mol. Biol. 2018, 25, 454, DOI: 10.1038/s41594-018-0061-5[Crossref], [PubMed], [CAS], Google Scholar207bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtlKqu7nL&md5=b3f9198f55998306f3b881c256be22a9The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitorsHansen, Rasmus; Peters, Ulf; Babbar, Anjali; Chen, Yuching; Feng, Jun; Janes, Matthew R.; Li, Lian-Sheng; Ren, Pingda; Liu, Yi; Zarrinkar, Patrick P.Nature Structural & Molecular Biology (2018), 25 (6), 454-462CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small mols.; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biol. activity of these inhibitors has been described, the biochem. mechanism of how the compds. achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chem. reaction with Cys12 in human KRASG12C, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small mols. can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable.
- 208Brameld, K. A.; Owens, T. D.; Verner, E.; Venetsanakos, E.; Bradshaw, J. M.; Phan, V. T.; Tam, D.; Leung, K.; Shu, J.; LaStant, J.; Loughhead, D. G.; Ton, T.; Karr, D. E.; Gerritsen, M. E.; Goldstein, D. M.; Funk, J. O. Discovery of the irreversible covalent FGFR inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido [2,3-d]pyrimidin-7(8H)-one (PRN1371) for the treatment of solid tumors. J. Med. Chem. 2017, 60, 6516– 6527, DOI: 10.1021/acs.jmedchem.7b00360[ACS Full Text], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVykt7fK&md5=987069b645d5e0e36ccda5e5c81520b9Discovery of the Irreversible Covalent FGFR Inhibitor 8-(3-(4-Acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (PRN1371) for the Treatment of Solid TumorsBrameld, Ken A.; Owens, Timothy D.; Verner, Erik; Venetsanakos, Eleni; Bradshaw, J. Michael; Phan, Vernon T.; Tam, Danny; Leung, Kwan; Shu, Jin; LaStant, Jacob; Loughhead, David G.; Ton, Tony; Karr, Dane E.; Gerritsen, Mary E.; Goldstein, David M.; Funk, Jens OliverJournal of Medicinal Chemistry (2017), 60 (15), 6516-6527CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clin. validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncol. indications. An irreversible covalent binding mechanism imparts many desirable pharmacol. benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chem. optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compd. 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.
- 209Wolle, P.; Hardick, J.; Cronin, S. J. F.; Engel, J.; Baumann, M.; Lategahn, J.; Penninger, J.; Rauh, D. Targeting the MKK7-JNK (Mitogen-Activated Protein Kinase Kinase 7-c Jun N-Terminal Kinase) pathway with covalent inhibitors. J. Med. Chem. 2019, 62, 2843, DOI: 10.1021/acs.jmedchem.9b00102[ACS Full Text], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFCqt70%253D&md5=9705c21d5e8df1b3b2f80e1125e66c74Targeting the MKK7-JNK (mitogen-activated protein kinase kinase 7-c-Jun N-terminal kinase) pathway with covalent inhibitorsWolle, Patrik; Hardick, Julia; Cronin, Shane J. F.; Engel, Julian; Baumann, Matthias; Lategahn, Jonas; Penninger, Josef M.; Rauh, DanielJournal of Medicinal Chemistry (2019), 62 (5), 2843-2848CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The protein kinase MKK7 is linked to neuronal development and the onset of cancer. The field, however, lacks high-quality functional probes that would allow for the dissection of its detailed functions. Against this background, we describe an effective covalent inhibitor of MKK7 based on the pyrazolopyrimidine scaffold.
- 210Lelais, G.; Epple, R.; Marsilje, T. H.; Long, Y. O.; McNeill, M.; Chen, B.; Lu, W.; Anumolu, J.; Badiger, S.; Bursulaya, B.; DiDonato, M.; Fong, R.; Juarez, J.; Li, J.; Manuia, M.; Mason, D. E.; Gordon, P.; Groessl, T.; Johnson, K.; Jia, Y.; Kasibhatla, S.; Li, C.; Isbell, J.; Spraggon, G.; Bender, S.; Michellys, P. Y. Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a novel, potent, and wt sparing covalent inhibitor of oncogenic (L858R, ex19del) and resistant (T790M) EGFR nutants for the treatment of EGFR mutant non-small-cell lung cancers. J. Med. Chem. 2016, 59, 6671– 6689, DOI: 10.1021/acs.jmedchem.5b01985[ACS Full Text], [CAS], Google Scholar210https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFOgu77P&md5=c106545d878ab3d675644b47099668a0Discovery of (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent, and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small-Cell Lung CancersLelais, Gerald; Epple, Robert; Marsilje, Thomas H.; Long, Yun O.; McNeill, Matthew; Chen, Bei; Lu, Wenshuo; Anumolu, Jaganmohan; Badiger, Sangamesh; Bursulaya, Badry; DiDonato, Michael; Fong, Rina; Juarez, Jose; Li, Jie; Manuia, Mari; Mason, Daniel E.; Gordon, Perry; Groessl, Todd; Johnson, Kevin; Jia, Yong; Kasibhatla, Shailaja; Li, Chun; Isbell, John; Spraggon, Glen; Bender, Steven; Michellys, Pierre-YvesJournal of Medicinal Chemistry (2016), 59 (14), 6671-6689CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through mol. docking studies we converted a mutant-selective high-throughput screening hit (7) into a no. of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compds. with good tolerability and efficacy that ultimately led to the selection of 47 as the clin. candidate.
- 211Horton, J. R.; Woodcock, C. B.; Chen, Q.; Liu, X.; Zhang, X.; Shanks, J.; Rai, G.; Mott, B. T.; Jansen, D. J.; Kales, S. C.; Henderson, M. J.; Cyr, M.; Pohida, K.; Hu, X.; Shah, P.; Xu, X.; Jadhav, A.; Maloney, D. J.; Hall, M. D.; Simeonov, A.; Fu, H.; Vertino, P. M.; Cheng, X. Structure-based engineering of irreversible inhibitors against histone lysine demethylase KDM5A. J. Med. Chem. 2018, 61, 10588, DOI: 10.1021/acs.jmedchem.8b01219[ACS Full Text], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2rur3P&md5=5ab97cae54ccff28f65071fa41a70c0aStructure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5AHorton, John R.; Woodcock, Clayton B.; Chen, Qin; Liu, Xu; Zhang, Xing; Shanks, John; Rai, Ganesha; Mott, Bryan T.; Jansen, Daniel J.; Kales, Stephen C.; Henderson, Mark J.; Cyr, Matthew; Pohida, Katherine; Hu, Xin; Shah, Pranav; Xu, Xin; Jadhav, Ajit; Maloney, David J.; Hall, Matthew D.; Simeonov, Anton; Fu, Haian; Vertino, Paula M.; Cheng, XiaodongJournal of Medicinal Chemistry (2018), 61 (23), 10588-10601CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The active sites of hundreds of human α-ketoglutarate (αKG) and Fe(II)-dependent dioxygenases are exceedingly well preserved, which challenges the design of selective inhibitors. We identified a noncatalytic cysteine (Cys481 in KDM5A) near the active sites of KDM5 histone H3 lysine 4 demethylases, which is absent in other histone demethylase families, that could be explored for interaction with the cysteine-reactive electrophile acrylamide. We synthesized analogs of a thienopyridine-based inhibitor chemotype, namely, 2-((3-aminophenyl)(2-(piperidin-1-yl)ethoxy)methyl)thieno[3,2-b]pyridine-7-carboxylic acid (N70) and a deriv. contg. a ((dimethylamino)but-2-enamido)phenyl moiety (N71) designed to form a covalent interaction with Cys481. We characterized the inhibitory and binding activities against KDM5A and detd. the cocrystal structures of the catalytic domain of KDM5A in complex with N70 and N71. Whereas the noncovalent inhibitor N70 displayed αKG-competitive inhibition that could be reversed after dialysis, inhibition by N71 was dependent on enzyme concn. and persisted even after dialysis, consistent with covalent modification.
- 212Liu, Y.; Xie, Z.; Zhao, D.; Zhu, J.; Mao, F.; Tang, S.; Xu, H.; Luo, C.; Geng, M.; Huang, M.; Li, J. Development of the first generation of disulfide-based subtype-selective and potent covalent pyruvate dehydrogenase kinase 1 (PDK1) inhibitors. J. Med. Chem. 2017, 60, 2227– 2244, DOI: 10.1021/acs.jmedchem.6b01245[ACS Full Text], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXjtlyjtr0%253D&md5=7529ce2fc9d1a138a8d1405a23f7e4e8Development of the First Generation of Disulfide-Based Subtype-Selective and Potent Covalent Pyruvate Dehydrogenase Kinase 1 (PDK1) InhibitorsLiu, Yifu; Xie, Zuoquan; Zhao, Dan; Zhu, Jin; Mao, Fei; Tang, Shuai; Xu, Hui; Luo, Cheng; Geng, Meiyu; Huang, Min; Li, JianJournal of Medicinal Chemistry (2017), 60 (6), 2227-2244CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pyruvate dehydrogenase kinases (PDKs) are overexpressed in most cancer cells and are responsible for aberrant glucose metab. The authors previously described Bis(4-morpholinyl thiocarbonyl)-disulfide (JX06, 16) as the first covalent inhibitor of PDK1. Here, based on the scaffold of JX06, the authors identify two novel types of disulfide-based PDK1 inhibitors. The most potent analog, bis(1,4-oxazepan-4-yl-thiocarbonyl)disulfide (3a), effectively inhibits PDK1 both at the mol. (kinact/Ki = 4.17 × 103 M-1s-1) and the cellular level (down to 0.1 μM). In contrast to JX06, 3a is a potent and subtype-selective inhibitor of PDK1 with >40-fold selectivity for PDK2-4. Compd. 3a also significantly alters glucose metabolic pathways in A549 cells by decreasing ECAR and increasing ROS. Moreover, in the xenograft models, 3a shows significant antitumor activity with no neg. effect to the mice wt. Collectively, these data demonstrate that 3a may be an excellent lead compd. for the treatment of cancer as a first-generation subtype-selective and covalent PDK1 inhibitor.
- 213(a) McAllister, L. A.; O’Neil, S. V.; Fonseca, K. R.; Piro, J. R.; Cianfrogna, J. A.; Foley, T. L.; Gilbert, A. M.; Harris, A. R.; Helal, C. J.; Johnson, D. S.; Montgomery, J. I.; Nason, D. M.; Noell, S.; Pandit, J.; Rogers, B. N.; Samad, T. A.; Shaffer, C. L.; da Silva, R. G.; Uccello, D. P.; Webb, D.; Brodney, M. A. Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation. J. Med. Chem. 2018, 61, 3008– 3026, DOI: 10.1021/acs.jmedchem.8b00070[ACS Full Text.], [CAS], Google Scholar213ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjslKlurw%253D&md5=984babc4de306b698756e9c2a9fc5c8eDiscovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of NeuroinflammationMcAllister, Laura A.; Butler, Christopher R.; Mente, Scot; O'Neil, Steven V.; Fonseca, Kari R.; Piro, Justin R.; Cianfrogna, Julie A.; Foley, Timothy L.; Gilbert, Adam M.; Harris, Anthony R.; Helal, Christopher J.; Johnson, Douglas S.; Montgomery, Justin I.; Nason, Deane M.; Noell, Stephen; Pandit, Jayvardhan; Rogers, Bruce N.; Samad, Tarek A.; Shaffer, Christopher L.; da Silva, Rafael G.; Uccello, Daniel P.; Webb, Damien; Brodney, Michael A.Journal of Medicinal Chemistry (2018), 61 (7), 3008-3026CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compd. I (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochem. property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving soly., and minimizing chem. lability. Compd. I achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.(b) Butler, C. R.; Beck, E. M.; Harris, A.; Huang, Z.; McAllister, L. A.; Am Ende, C. W.; Fennell, K.; Foley, T. L.; Fonseca, K.; Hawrylik, S. J.; Johnson, D. S.; Knafels, J. D.; Mente, S.; Noell, G. S.; Pandit, J.; Phillips, T. B.; Piro, J. R.; Rogers, B. N.; Samad, T. A.; Wang, J.; Wan, S.; Brodney, M. A. Azetidine and piperidine carbamates as efficient, covalent inhibitors of monoacylglycerol lipase. J. Med. Chem. 2017, 60, 9860– 9873, DOI: 10.1021/acs.jmedchem.7b01531[ACS Full Text], [CAS], Google Scholar213bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWqurzO&md5=b89f7d44f611dd84cd49a8d240ac26b0Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol LipaseButler, Christopher R.; Beck, Elizabeth M.; Harris, Anthony; Huang, Zhen; McAllister, Laura A.; am Ende, Christopher W.; Fennell, Kimberly; Foley, Timothy L.; Fonseca, Kari; Hawrylik, Steven J.; Johnson, Douglas S.; Knafels, John D.; Mente, Scot; Noell, G. Stephen; Pandit, Jayvardhan; Phillips, Tracy B.; Piro, Justin R.; Rogers, Bruce N.; Samad, Tarek A.; Wang, Jane; Wan, Shuangyi; Brodney, Michael A.Journal of Medicinal Chemistry (2017), 60 (23), 9860-9873CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degrdn. of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein the authors describe highly efficient MAGL inhibitors, identified through a parallel medicinal chem. approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compd. 6 (1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-phenyl-1H-pyrazol-3-yl)azetidine-1-carboxylate), a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.
- 214Kulkarni, P. M.; Kulkarni, A. R.; Korde, A.; Tichkule, R. B.; Laprairie, R. B.; Denovan-Wright, E. M.; Zhou, H.; Janero, D. R.; Zvonok, N.; Makriyannis, A.; Cascio, M. G.; Pertwee, R. G.; Thakur, G. A. Novel electrophilic and photoaffinity covalent probes for mapping the cannabinoid 1 receptor allosteric site(s). J. Med. Chem. 2016, 59, 44– 60, DOI: 10.1021/acs.jmedchem.5b01303[ACS Full Text], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslKlsbvN&md5=bdd1f5e67ef28ecf57773817c7c2c00fNovel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s)Kulkarni, Pushkar M.; Kulkarni, Abhijit R.; Korde, Anisha; Tichkule, Ritesh B.; Laprairie, Robert B.; Denovan-Wright, Eileen M.; Zhou, Han; Janero, David R.; Zvonok, Nikolai; Makriyannis, Alexandros; Cascio, Maria G.; Pertwee, Roger G.; Thakur, Ganesh A.Journal of Medicinal Chemistry (2016), 59 (1), 44-60CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Undesirable side effects assocd. with orthosteric agonists/antagonists of cannabinoid 1 receptor (CB1R), a tractable target for treating several pathologies affecting humans, have greatly limited their translational potential. Recent discovery of CB1R neg. allosteric modulators (NAMs) has renewed interest in CB1R by offering a potentially safer therapeutic avenue. To elucidate the CB1R allosteric binding motif and thereby facilitate rational drug discovery, we report the synthesis and biochem. characterization of first covalent ligands designed to bind irreversibly to the CB1R allosteric site. Either an electrophilic or a photoactivatable group was introduced at key positions of two classical CB1R NAMs: Org27569 (1) and PSNCBAM-1 (2). Among these, 20 (GAT100) emerged as the most potent NAM in functional assays, did not exhibit inverse agonism, and behaved as a robust pos. allosteric modulator of binding of orthosteric agonist CP55,940. This novel covalent probe can serve as a useful tool for characterizing CB1R allosteric ligand-binding motifs.
- 215Doornbos, M. L. J.; Wang, X.; Vermond, S. C.; Peeters, L.; Pérez-Benito, L.; Trabanco, A. A.; Lavreysen, H.; Cid, J. M.; Heitman, L. H.; Tresadern, G.; IJzerman, A. P. Covalent allosteric probe for the metabotropic glutamate receptor 2: Design, synthesis, and pharmacological characterization. J. Med. Chem. 2019, 62, 223, DOI: 10.1021/acs.jmedchem.8b00051[ACS Full Text], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjs1Cgs78%253D&md5=5d4cafa60439bbcdb81667789326099aCovalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological CharacterizationDoornbos, Maarten L. J.; Wang, Xuesong; Vermond, Sophie C.; Peeters, Luc; Perez-Benito, Laura; Trabanco, Andres A.; Lavreysen, Hilde; Cid, Jose Maria; Heitman, Laura H.; Tresadern, Gary; IJzerman, Adriaan P.Journal of Medicinal Chemistry (2019), 62 (1), 223-233CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Covalent labeling of G protein-coupled receptors (GPCRs) by small mols. is a powerful approach to understand binding modes, mechanism of action, pharmacol., and even facilitate structure elucidation. We report the first covalent pos. allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacol. characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compd. in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chem. biol. approaches.
- 216Casimiro-Garcia, A.; Trujillo, J. I.; Vajdos, F.; Juba, B.; Banker, M. E.; Aulabaugh, A.; Balbo, P.; Bauman, J.; Chrencik, J.; Coe, J. W.; Czerwinski, R.; Dowty, M.; Knafels, J. D.; Kwon, S.; Leung, L.; Liang, S.; Robinson, R. P.; Telliez, J. B.; Unwalla, R.; Yang, X.; Thorarensen, A. Identification of cyanamide-based Janus kinase 3 (JAK3) covalent inhibitors. J. Med. Chem. 2018, 61, 10665, DOI: 10.1021/acs.jmedchem.8b01308[ACS Full Text], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitF2qtrjK&md5=12832ed66b8fc89d5f6ef9a3aa4ea20fIdentification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent InhibitorsCasimiro-Garcia, Agustin; Trujillo, John I.; Vajdos, Felix; Juba, Brian; Banker, Mary Ellen; Aulabaugh, Ann; Balbo, Paul; Bauman, Jonathan; Chrencik, Jill; Coe, Jotham W.; Czerwinski, Robert; Dowty, Martin; Knafels, John D.; Kwon, Soojin; Leung, Louis; Liang, Sidney; Robinson, Ralph P.; Telliez, Jean-Baptiste; Unwalla, Ray; Yang, Xin; Thorarensen, AtliJournal of Medicinal Chemistry (2018), 61 (23), 10665-10699CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallog., kinetic, and computational studies, interaction of cyanamide I with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by II. In relevant cell-based assays and in agreement with previous results from this group, II demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for I. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
- 217Chan, A. H.; Lee, W. G.; Spasov, K. A.; Cisneros, J. A.; Kudalkar, S. N.; Petrova, Z. O.; Buckingham, A. B.; Anderson, K. S.; Jorgensen, W. Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: from design to protein crystallography. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 9725– 9730, DOI: 10.1073/pnas.1711463114[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlOhtbnM&md5=e3adcd94ed487e866026a3d46f4e09d8Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallographyChan, Albert H.; Lee, Won-Gil; Spasov, Krasimir A.; Cisneros, Jose A.; Kudalkar, Shalley N.; Petrova, Zaritza O.; Buckingham, Amanda B.; Anderson, Karen S.; Jorgensen, William L.Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (36), 9725-9730CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance assocd. with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, esp. in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallog., and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.
- 218Shindo, N.; Fuchida, H.; Sato, M.; Watari, K.; Shibata, T.; Kuwata, K.; Miura, C.; Okamoto, K.; Hatsuyama, Y.; Tokunaga, K.; Sakamoto, S.; Morimoto, S.; Abe, Y.; Shiroishi, M.; Caaveiro, J. M. M.; Ueda, T.; Tamura, T.; Matsunaga, N.; Nakao, T.; Koyanagi, S.; Ohdo, S.; Yamaguchi, Y.; Hamachi, I.; Ono, M.; Ojida, A. Selective and reversible modification of kinase cysteines with chlorofluoroacetamides. Nat. Chem. Biol. 2019, 15, 250, DOI: 10.1038/s41589-018-0204-3[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXlvFSgur4%253D&md5=f6c8886d540ea26a8abecd950feba913Selective and reversible modification of kinase cysteines with chlorofluoroacetamidesShindo, Naoya; Fuchida, Hirokazu; Sato, Mami; Watari, Kosuke; Shibata, Tomohiro; Kuwata, Keiko; Miura, Chizuru; Okamoto, Kei; Hatsuyama, Yuji; Tokunaga, Keisuke; Sakamoto, Seiichi; Morimoto, Satoshi; Abe, Yoshito; Shiroishi, Mitsunori; Caaveiro, Jose M. M.; Ueda, Tadashi; Tamura, Tomonori; Matsunaga, Naoya; Nakao, Takaharu; Koyanagi, Satoru; Ohdo, Shigehiro; Yamaguchi, Yasuchika; Hamachi, Itaru; Ono, Mayumi; Ojida, AkioNature Chemical Biology (2019), 15 (3), 250-258CODEN: NCBABT; ISSN:1552-4450. (Nature Research)Irreversible inhibition of disease-assocd. proteins with small mols. is a powerful approach for achieving increased and sustained pharmacol. potency. Here, we introduce α-chlorofluoroacetamide (CFA) as a novel warhead of targeted covalent inhibitor (TCI). Despite weak intrinsic reactivity, CFA-appended quinazoline showed high reactivity toward Cys797 of epidermal growth factor receptor (EGFR). In cells, CFA-quinazoline showed higher target specificity for EGFR than the corresponding Michael acceptors in a wide concn. range (0.1-10 μM). The cysteine adduct of the CFA deriv. was susceptible to hydrolysis and reversibly yielded intact thiol but was stable in solvent-sequestered ATP-binding pocket of EGFR. This environment-dependent hydrolysis can potentially reduce off-target protein modification by CFA-based drugs. Oral administration of CFA quinazoline, (2R)-1-(2-chloro-2-fluoroacetyl)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)-propoxy]quinazolin-6-yl]pyrrolidine-2-carboxamide [2226257-92-5] (NS-062, compd. 51) significantly suppressed tumor growth in a mouse xenograft model. Further, CFA-appended pyrazolopyrimidine irreversibly inhibited Bruton's tyrosine kinase with higher target specificity. These results demonstrate the utility of CFA as a new class warheads for TCI.
- 219(a) Brouwer, A. J.; Jonker, A.; Werkhoven, P.; Kuo, E.; Li, N.; Gallastegui, N.; Kemmink, J.; Florea, B. I.; Groll, M.; Overkleeft, H. S.; Liskamp, R. M. Peptido sulfonyl fluorides as new powerful proteasome inhibitors. J. Med. Chem. 2012, 55, 10995– 1003, DOI: 10.1021/jm301443r[ACS Full Text.], [CAS], Google Scholar219ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslalurjE&md5=e84873c90746c6642013c03b51b40bcfPeptido sulfonyl fluorides as new powerful proteasome inhibitorsBrouwer, Arwin J.; Jonker, Anika; Werkhoven, Paul; Kuo, Ethan; Li, Nan; Gallastegui, Nerea; Kemmink, Johan; Florea, Bogdan I.; Groll, Michael; Overkleeft, Herman S.; Liskamp, Rob M. J.Journal of Medicinal Chemistry (2012), 55 (24), 10995-11003CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A new class of potent proteasome inhibitors is described, of which the members contain an amino acid inspired sulfonyl fluoride as the electrophilic trap. In total, 24 peptido sulfonyl fluoride inhibitors have been designed and synthesized, which were inspired by the backbone sequences of the proteasome inhibitors bortezomib, epoxomicin, and Cbz-Leu3-aldehyde. Nine of them were very potent proteasome inhibitors, the best of which had an IC50 of 7 nM. A no. of the peptido sulfonyl fluoride inhibitors were found to be highly selective for the β5 proteasome subunit.(b) Artschwager, R.; Ward, D.; Gannon, S.; Brouwer, A. J.; van de Langemheen, H.; Kowalski, H.; Liskamp, R. Potent and highly selective inhibitors of the proteasome trypsin-like site by incorporation of basic side chain containing amino acid derived sulfonyl fluorides. J. Med. Chem. 2018, 61, 5395– 5411, DOI: 10.1021/acs.jmedchem.8b00685[ACS Full Text], [CAS], Google Scholar219bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpvVGktrc%253D&md5=eb1a22968da0b5b4622e4f9b65af7326Potent and Highly Selective Inhibitors of the Proteasome Trypsin-like Site by Incorporation of Basic Side Chain Containing Amino Acid Derived Sulfonyl FluoridesArtschwager, Raik; Ward, David J.; Gannon, Susan; Brouwer, Arwin J.; van de Langemheen, Helmus; Kowalski, Hubert; Liskamp, Rob M. J.Journal of Medicinal Chemistry (2018), 61 (12), 5395-5411CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A unique category of basic side chain contg. amino acid derived sulfonyl fluorides (SFs) has been synthesized for incorporation into new proteasome inhibitors targeting the trypsin-like site of the 20S proteasome. Masking the former α-amino functionality of the amino acid starting derivs. as an azido functionality allowed an elegant conversion to the corresponding amino acid derived sulfonyl fluorides. The inclusion of different SFs at the P1 site of a proteasome inhibitor resulted in 14 different peptidosulfonyl fluorides (PSFs) having a high potency and an excellent selectivity for the proteolytic activity of the β2 subunit over that of the β5 subunit. The results of this study strongly indicate that a free N-terminus of PSFs inhibitors is crucial for high selectivity toward the trypsin-like site of the 20S proteasome. Nevertheless, all compds. are slightly more selective for inhibition of the constitutive over the immunoproteasome.
- 220Yang, F.; Zhu, M.; Zhang, J.; Zhou, H. Synthesis of biologically active boron-containing compounds. MedChemComm 2018, 9, 201– 211, DOI: 10.1039/C7MD00552K[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVOrt7jN&md5=11018b19779619600cdb63d60ae07407Synthesis of biologically active boron-containing compoundsYang, Fei; Zhu, Mingyan; Zhang, Jinyi; Zhou, HuchenMedChemComm (2018), 9 (2), 201-211CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)Boron-contg. compds. which possess unique and attractive properties have received increasing attention from the pharmaceutical industry and academia recently. They have shown interesting and useful biol. activities, including antibacterial, antifungal, antiparasitic, antiviral, and anti-inflammatory activities. In this review, the synthetic strategies for various boron-contg. compds., including peptidyl boronic acids, benzoxaboroles, benzoxaborines, benzodiazaborines, amine carboxyboranes, and amine cyanoboranes are summarized. Representative structures of each structural class and recently developed biol. active boron-contg. compds. are used as examples in this review.
- 221(a) Smith, T. P.; Windsor, I. W.; Forest, K. T.; Raines, R. T. Stilbene boronic acids form a covalent bond with human transthyretin and inhibit its aggregation. J. Med. Chem. 2017, 60, 7820– 7834, DOI: 10.1021/acs.jmedchem.7b00952[ACS Full Text.], [CAS], Google Scholar221ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2lur%252FN&md5=63d28cf990198b6e0dce953af76fb752Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its AggregationSmith, Thomas P.; Windsor, Ian W.; Forest, Katrina T.; Raines, Ronald T.Journal of Medicinal Chemistry (2017), 60 (18), 7820-7834CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Transthyretin (TTR) is a homotetrameric protein. Its dissocn. into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small mols. to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallog. anal. of nine TTR·ligand complexes. The ensuing structure-function data led to a sym. diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-mol. drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.(b) Windsor, I. W.; Palte, M. J.; Lukesh, J. C., 3rd.; Gold, B.; Forest, K. T.; Raines, R. T. Sub-picomolar inhibition of hiv-1 protease with a boronic acid. J. Am. Chem. Soc. 2018, 140, 14015– 14018, DOI: 10.1021/jacs.8b07366[ACS Full Text], [CAS], Google Scholar221bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFaltbnI&md5=ad7d7a58f8e3cad8c6fea7cb2823741cSub-picomolar Inhibition of HIV-1 Protease with a Boronic AcidWindsor, Ian W.; Palte, Michael J.; Lukesh, John C.; Gold, Brian; Forest, Katrina T.; Raines, Ronald T.Journal of the American Chemical Society (2018), 140 (43), 14015-14018CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallog. demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short (rO···O = 2.2 Å), and d. functional theory anal. reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-mol. ligands.
- 222Nitsche, C.; Zhang, L.; Weigel, L. F.; Schilz, J.; Graf, D.; Bartenschlager, R.; Hilgenfeld, R.; Klein, C. D. Peptide-boronic acid inhibitors of flaviviral proteases: medicinal chemistry and structural biology. J. Med. Chem. 2017, 60, 511– 516, DOI: 10.1021/acs.jmedchem.6b01021[ACS Full Text], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvFGrtLvE&md5=a9671140deb2c9014ae8e1429cb5074fPeptide-Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural BiologyNitsche, Christoph; Zhang, Linlin; Weigel, Lena F.; Schilz, Jonas; Graf, Dominik; Bartenschlager, Ralf; Hilgenfeld, Rolf; Klein, Christian D.Journal of Medicinal Chemistry (2017), 60 (1), 511-516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A thousand-fold affinity gain is achieved by introduction of a C-terminal boronic acid moiety into dipeptidic inhibitors of the Zika, West Nile and dengue virus proteases. The resulting compds. have Ki values in the two-digit nanomolar range, are not cytotoxic, and inhibit virus replication. Structure-activity relationships and a high resoln. x-ray co-crystal structure with West Nile virus protease provide a basis for the design of optimized covalent-reversible inhibitors aimed at emerging flaviviral pathogens.
- 223Zervosen, A.; Herman, R.; Kerff, F.; Herman, A.; Bouillez, A.; Prati, F.; Pratt, R. F.; Frère, J. M.; Joris, B.; Luxen, A.; Charlier, P.; Sauvage, E. Unexpected tricovalent binding mode of boronic acids within the active site of a penicillin-binding protein. J. Am. Chem. Soc. 2011, 133, 10839– 10848, DOI: 10.1021/ja200696y[ACS Full Text], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvFKhsr0%253D&md5=847cbfcb9458d610240b34d01a99a261Unexpected Tricovalent Binding Mode of Boronic Acids within the Active Site of a Penicillin-Binding ProteinZervosen, Astrid; Herman, Raphael; Kerff, Frederic; Herman, Alexandre; Bouillez, Andre; Prati, Fabio; Pratt, R. F.; Frere, Jean-Marie; Joris, Bernard; Luxen, Andre; Charlier, Paulette; Sauvage, EricJournal of the American Chemical Society (2011), 133 (28), 10839-10848CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Boronic acids bearing appropriate side chains are good inhibitors of serine amidohydrolases. The boron usually adopts a tetrahedral conformation, bound to the nucleophilic serine of the active site and mimicking the transition state of the enzymic reaction. We have solved the structures of complexes of a penicillin-binding protein (PBP), the DD-peptidase from Actinomadura sp. R39, with four amidomethylboronic acids (2,6-dimethoxybenzamidomethylboronic acid, phenylacetamidomethylboronic acid, 2-chlorobenzamidomethylboronic acid, and 2-nitrobenzamidomethylboronic acid) and the pinacol ester derived from phenylacetamidomethylboronic acid. We found that in each case, the boron forms a tricovalent adduct with the Oγ from Ser49 and Ser298, and the terminal amine group of Lys410, three key residues involved in the catalytic mechanism of penicillin-binding proteins. This represents the first tricovalent enzyme-inhibitor adducts obsd. by crystallog. In two of the five R39-boronate structures, the boronic acid is found as a tricovalent adduct in two monomers of the asym. unit and as a monocovalent adduct with the active serine in the two remaining monomers of the asym. unit. Formation of the tricovalent complex from a classical monocovalent complex may involve rotation around the Ser49 Cα-Cβ bond to place the boron in a position to interact with Ser298 and Lys410, and a twisting of the side-chain amide such that its carbonyl oxygen is able to hydrogen bond to the oxyanion hole NH of Thr413. Biphasic kinetics were obsd. in three of the five cases, and details of the reaction between R39 and 2,6-dimethoxybenzamidomethylboronic acid were studied. Observation of biphasic kinetics was not, however, thought to be correlated with formation of tricovalent complexes, assuming that the latter do form in soln. On the basis of the crystallog. and kinetic results, a reaction scheme for this unexpected inhibition by boronic acids is proposed.
- 224(a) Powers, R. A.; Swanson, H. C.; Taracila, M. A.; Florek, N. W.; Romagnoli, C.; Caselli, E.; Prati, F.; Bonomo, R. A.; Wallar, B. J. Biochemical and structural analysis of inhibitors targeting the ADC-7 cephalosporinase of Acinetobacter baumannii. Biochemistry 2014, 53, 7670– 7679, DOI: 10.1021/bi500887n[ACS Full Text.], [CAS], Google Scholar224ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhvVyrtLnJ&md5=9b36ea9ec80e8f17308f9c1e0e2f6298Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumanniiPowers, Rachel A.; Swanson, Hollister C.; Taracila, Magdalena A.; Florek, Nicholas W.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Bonomo, Robert A.; Wallar, Bradley J.Biochemistry (2014), 53 (48), 7670-7679CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)β-Lactam resistance in Acinetobacter baumannii presents one of the greatest challenges to contemporary antimicrobial chemotherapy. Much of this resistance to cephalosporins derives from the expression of the class C β-lactamase enzymes, known as Acinetobacter-derived cephalosporinases (ADCs). Currently, β-lactamase inhibitors are structurally similar to β-lactam substrates and are not effective inactivators of this class C cephalosporinase. Herein, two boronic acid transition state inhibitors (BATSIs S02030 and SM23) that are chem. distinct from β-lactams were designed and tested for inhibition of ADC enzymes. BATSIs SM23 and S02030 bind with high affinity to ADC-7, a chromosomal cephalosporinase from Acinetobacter baumannii (Ki = 21.1 ± 1.9 nM and 44.5 ± 2.2 nM, resp.). The X-ray crystal structures of ADC-7 were detd. in both the apo form (1.73 Å resoln.) and in complex with S02030 (2.0 Å resoln.). In the complex, S02030 makes several canonical interactions: the O1 oxygen of S02030 is bound in the oxyanion hole, and the R1 amide group makes key interactions with conserved residues Asn152 and Gln120. In addn., the carboxylate group of the inhibitor is meant to mimic the C3/C4 carboxylate found in β-lactams. The C3/C4 carboxylate recognition site in class C enzymes is comprised of Asn346 and Arg349 (AmpC numbering), and these residues are conserved in ADC-7. Interestingly, in the ADC-7/S02030 complex, the inhibitor carboxylate group is obsd. to interact with Arg340, a residue that distinguishes ADC-7 from the related class C enzyme AmpC. A thermodn. anal. suggests that ΔH driven compds. may be optimized to generate new lead agents. The ADC-7/BATSI complex provides insight into recognition of non-β-lactam inhibitors by ADC enzymes and offers a starting point for the structure-based optimization of this class of novel β-lactamase inhibitors against a key resistance target.(b) Caselli, E.; Romagnoli, C.; Vahabi, R.; Taracila, M. A.; Bonomo, R. A.; Prati, F. Click chemistry in lead optimization of boronic acids as β-lactamase inhibitors. J. Med. Chem. 2015, 58, 5445– 5458, DOI: 10.1021/acs.jmedchem.5b00341[ACS Full Text.], [CAS], Google Scholar224bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKit7nM&md5=b2499e36d43734a1ea8b706b73e454feClick Chemistry in Lead Optimization of Boronic Acids as β-Lactamase InhibitorsCaselli, Emilia; Romagnoli, Chiara; Vahabi, Roza; Taracila, Magdalena A.; Bonomo, Robert A.; Prati, FabioJournal of Medicinal Chemistry (2015), 58 (14), 5445-5458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Boronic acid transition-state inhibitors (BATSIs) represent one of the most promising classes of β-lactamase inhibitors. Here the authors describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic acids, which were synthesized by combining the asym. homologation of boronates with Cu-catalyzed azide-alkyne cycloaddn. for the stereoselective insertion of the amido group and the regioselective formation of the 1,4-disubstituted triazole, resp. This synthetic pathway, which avoids intermediate purifications, proved to be flexible and efficient, affording in good yields a panel of 14 BATSIs bearing three different R1 amide side chains (acetamido, benzylamido, and 2-thienylacetamido) and several R substituents on the triazole. This small library was tested against two clin. relevant class C β-lactamases from Enterobacter spp. and Pseudomonas aeruginosa. The Ki value of the best compd. (13a) was ≥4 nM with significant redn. of bacterial resistance to the combination of cefotaxime/13a.(c) Bouza, A. A.; Swanson, H. C.; Smolen, K. A.; VanDine, A. L.; Taracila, M. A.; Romagnoli, C.; Caselli, E.; Prati, F.; Bonomo, R. A.; Powers, R. A.; Wallar, B. J. Structure-based analysis of boronic acids as inhibitors of acinetobacter-derived cephalosporinase-7, a unique class C β-lactamase. ACS Infect. Dis. 2018, 4, 325– 336, DOI: 10.1021/acsinfecdis.7b00152[ACS Full Text.], [CAS], Google Scholar224chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWntrfF&md5=6453dfb5439845b40e5a9085470cf5ffStructure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-LactamaseBouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; VanDine, Alison L.; Taracila, Magdalena A.; Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio; Bonomo, Robert A.; Powers, Rachel A.; Wallar, Bradley J.ACS Infectious Diseases (2018), 4 (3), 325-336CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12,000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is a result of class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clin. used β-lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. Ki values ranged from low micromolar to sub-nanomolar, and CD (CD) demonstrated that each inhibitor stabilizes the β-lactamase-inhibitor complexes. Addnl., X-ray crystal structures of ADC-7 in complex with five inhibitors were detd. (resolns. from 1.80-2.09 Å). In the ADC-7/CR192 complex, the BATSI with the lowest Ki (0.45 nM) and greatest ΔTm (+9 °C), a trifluoromethyl substituent interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. The ADC-7/BATSI complexes detd. in this study shed light into the unique recognition sites in ADC enzymes, and also offer insight into further structure-based optimization of these inhibitors.(d) Caselli, E.; Romagnoli, C.; Powers, R. A.; Taracila, M. A.; Bouza, A. A.; Swanson, H. C.; Smolen, K. A.; Fini, F.; Wallar, B. J.; Bonomo, R. A.; Prati, F. Inhibition of acinetobacter-derived cephalosporinase: exploring the carboxylate recognition site using novel β-lactamase inhibitors. ACS Infect. Dis. 2018, 4, 337– 348, DOI: 10.1021/acsinfecdis.7b00153[ACS Full Text], [CAS], Google Scholar224dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWnt7nE&md5=d3f02a44ba426f305b6c43ea8f4b78fcInhibition of Acinetobacter-Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase InhibitorsCaselli, Emilia; Romagnoli, Chiara; Powers, Rachel A.; Taracila, Magdalena A.; Bouza, Alexandra A.; Swanson, Hollister C.; Smolen, Kali A.; Fini, Francesco; Wallar, Bradley J.; Bonomo, Robert A.; Prati, FabioACS Infectious Diseases (2018), 4 (3), 337-348CODEN: AIDCBC; ISSN:2373-8227. (American Chemical Society)Boronic acids are attracting a lot of attention as β-lactamase inhibitors, and in particular compd. S02030 (Ki = 44 nM) proved to be a good lead compd. against ADC-7 (Acinetobacter Derived Cephalosporinase), one of the most significant resistance determinants in A. baumannii. The at. structure of the ADC-7/S02030 complex highlighted the importance of crit. structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in β-lactams, we designed, synthesized, and characterized six derivs. of S02030 (3a). Out of the six compds., the best inhibitors proved to be those with an explicit neg. charge (compds. 3a-c and 3h,j, Ki = 44-115 nM), which is in contrast to the derivs. where the neg. charge is omitted, such as the amide deriv. 3d (Ki = 224 nM) and the hydroxyamide deriv. 3e (Ki = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compds. 3c, SM23, and EC04 were detd. All three compds. share the same structural features as in S02030, but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the neg. charged R2 side chain. This cephalosporinase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than binding site in ADC enzymes. Furthermore, this class of compds. was tested against resistant clin. strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a β-lactam antibiotic.
- 225Mons, E.; Jansen, I. D. C.; Loboda, J.; van Doodewaerd, B. R.; Hermans, J.; Verdoes, M.; van Boeckel, C. A. A.; van Veelen, P. A.; Turk, B.; Turk, D.; Ovaa, H. The alkyne moiety as a latent electrophile in irreversible covalent small molecule inhibitors of Cathepsin K. J. Am. Chem. Soc. 2019, 141, 3507, DOI: 10.1021/jacs.8b11027[ACS Full Text], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFKjtbY%253D&md5=3a18718aa722a8d46c5be1cf07dd077bThe Alkyne Moiety as a Latent Electrophile in Irreversible Covalent Small Molecule Inhibitors of Cathepsin KMons, Elma; Jansen, Ineke D. C.; Loboda, Jure; van Doodewaerd, Bjorn R.; Hermans, Jill; Verdoes, Martijn; van Boeckel, Constant A. A.; van Veelen, Peter A.; Turk, Boris; Turk, Dusan; Ovaa, HuibJournal of the American Chemical Society (2019), 141 (8), 3507-3514CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Irreversible covalent inhibitors can have a beneficial pharmacokinetic/pharmacodynamics profile but are still often avoided due to the risk of indiscriminate covalent reactivity and the resulting adverse effects. To overcome this potential liability, we introduced an alkyne moiety as a latent electrophile into small mol. inhibitors of cathepsin K (CatK). Alkyne-based inhibitors do not show indiscriminate thiol reactivity but potently inhibit CatK protease activity by formation of an irreversible covalent bond with the catalytic cysteine residue, confirmed by crystal structure anal. The rate of covalent bond formation (kinact) does not correlate with electrophilicity of the alkyne moiety, indicative of a proximity-driven reactivity. Inhibition of CatK-mediated bone resorption is validated in human osteoclasts. Together, this work illustrates the potential of alkynes as latent electrophiles in small mol. inhibitors, enabling the development of irreversible covalent inhibitors with an improved safety profile.
- 226Palermo, G.; Branduardi, D.; Masetti, M.; Lodola, A.; Mor, M.; Piomelli, D.; Cavalli, A.; De Vivo, M. Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas. J. Med. Chem. 2011, 54, 6612– 6623, DOI: 10.1021/jm2004283[ACS Full Text], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFCgsb3O&md5=3130e9ef929a52cc0900ad77b38a7453Covalent Inhibitors of Fatty Acid Amide Hydrolase: A Rationale for the Activity of Piperidine and Piperazine Aryl UreasPalermo, Giulia; Branduardi, Davide; Masetti, Matteo; Lodola, Alessio; Mor, Marco; Piomelli, Daniele; Cavalli, Andrea; De Vivo, MarcoJournal of Medicinal Chemistry (2011), 54 (19), 6612-6623CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and potent FAAH inhibitors (FAAHi), there are the cyclic piperidine and piperazine aryl ureas. FAAH hydrolyzes efficiently the amide bond of these compds., forming a covalent enzyme-inhibitor adduct. To rationalize this exptl. evidence, we performed an extensive computational anal. centered on piperidine-based PF750 (1) and piperazine-based JNJ1661010 (2), two potent lead compds. used to generate covalent inhibitors as clin. candidates. We found that FAAH induces a distortion of the amide bond of the piperidine and piperazine aryl ureas. Quantum mechanics/mol. mechanics ΔELUMO-HOMO energies indicate that the obsd. enzyme-induced distortion of the amide bond favors the formation of a covalent FAAH-inhibitor adduct. These findings could help in the rational structure-based design of novel covalent FAAHi.
- 227Chatterjee, P.; Botello-Smith, W. M.; Zhang, H.; Qian, L.; Alsamarah, A.; Kent, D.; Lacroix, J. J.; Baudry, M.; Luo, Y. Can relative binding free energy predict selectivity of reversible covalent inhibitors?. J. Am. Chem. Soc. 2017, 139, 17945– 17952, DOI: 10.1021/jacs.7b08938[ACS Full Text], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslyrs7bI&md5=e6a38ff570134e956eb43bd4a874ca55Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors?Chatterjee, Payal; Botello-Smith, Wesley M.; Zhang, Han; Qian, Li; Alsamarah, Abdelaziz; Kent, David; Lacroix, Jerome J.; Baudry, Michel; Luo, YunJournal of the American Chemical Society (2017), 139 (49), 17945-17952CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Reversible covalent inhibitors have many clin. advantages over noncovalent or irreversible covalent drugs. However, apart from selecting a warhead, substantial efforts in design and synthesis are needed to optimize noncovalent interactions to improve target-selective binding. Computational prediction of binding affinity for reversible covalent inhibitors presents a unique challenge since the binding process consists of multiple steps, which are not necessarily independent of each other. In this study, the authors lay out the relation between relative binding free energy and the overall reversible covalent binding affinity using a two-state binding model. To prove the concept, the authors employed free energy perturbation (FEP) coupled with λ-exchange mol. dynamics method to calc. the binding free energy of a series of α-ketoamide analogs relative to a common warhead scaffold, in both noncovalent and covalent binding states, and for two highly homologous proteases, calpain-1 and calpain-2. The authors conclude that covalent binding state alone, in general, can be used to predict reversible covalent binding selectivity. However, exceptions may exist. Therefore, the authors also discuss the conditions under which the noncovalent binding step is no longer negligible and propose to combine the relative FEP calcns. with a single QM/MM calcn. of warhead to predict the binding affinity and binding kinetics. The FEP calcns. also revealed that covalent and noncovalent binding states of an inhibitor do not necessarily exhibit the same selectivity. Thus, investigating both binding states, as well as the kinetics will provide extremely useful information for optimizing reversible covalent inhibitors.
- 228Scarpino, A.; Ferenczy, G. G.; Keseru, G. M. Comparative evaluation of covalent docking tools. J. Chem. Inf. Model. 2018, 58, 1441– 1458, DOI: 10.1021/acs.jcim.8b00228[ACS Full Text], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSmsLzE&md5=d74695be1f047ac840527161c510692dComparative Evaluation of Covalent Docking ToolsScarpino, Andrea; Ferenczy, Gyorgy G.; Keseru, Gyorgy M.Journal of Chemical Information and Modeling (2018), 58 (7), 1441-1458CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)Increased interest in covalent drug discovery led to the development of computer programs predicting binding mode and affinity of covalent inhibitors. Here we compare the performance of six covalent docking tools, AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE, for reproducing exptl. binding modes in an unprecedently large and diverse set of covalent complexes. It was found that 40-60% of the top scoring ligand poses are within 2.0 Å RMSD from the exptl. binding mode. This rate showed program dependent increase and achieved 50-90% when the best RMSD among the top ten scoring poses was considered. This performance is comparable to that of noncovalent docking tools and therefore suggests that anchoring the ligand does not necessarily improve the accuracy of the prediction. The effect of various ligand and protein features on the docking performance was investigated. At the level of warhead chem., higher success rate was found for Michael addns., nucleophilic addns. and nucleophilic substitutions than for ring opening reactions and disulfide formation. Increasing ligand size and flexibility generally affects pose predictions unfavorably, although AutoDock4, FITTED, and ICM-Pro were found to be less sensitive up to 35 heavy atoms. Increasing the accessibility of the target cysteine tends to result in improved binding mode predictions. Docking programs show protein dependent performance suggesting a target-dependent choice of the optimal docking tool. It was found that noncovalent docking into Cys/Ala mutated proteins by ICM-Pro and Glide reproduced exptl. binding modes with only slightly lower performance and at a significantly lower computational expense than covalent docking did. Overall, our results highlight the key factors influencing the docking performance of the investigated tools and they give guidelines for selecting the optimal combination of warheads, ligands, and tools for the system investigated. Results also identify the most important aspects to be considered for developing improved protocols for docking and virtual screening of covalent ligands.
- 229(a) Kathman, S. G.; Xu, Z.; Statsyuk, A. V. A fragment-based method to discover irreversible covalent inhibitors of cysteine proteases. J. Med. Chem. 2014, 57, 4969– 4974, DOI: 10.1021/jm500345q[ACS Full Text.], [CAS], Google Scholar229ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXovVWiur0%253D&md5=39dee964ac1ba26ed373eedbd86102acA Fragment-Based Method to Discover Irreversible Covalent Inhibitors of Cysteine ProteasesKathman, Stefan G.; Xu, Ziyang; Statsyuk, Alexander V.Journal of Medicinal Chemistry (2014), 57 (11), 4969-4974CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel fragment-based drug discovery approach is reported which irreversibly tethers drug-like fragments to catalytic cysteines. Acrylamides, acylaminoacrylates, vinylsulfonamides, and acylaminopropenyl sulfones were prepd. and the dependence of their rates of reaction with N-acetylcysteine Me ester on their structure was detd.; of the compds. tested, the rate of Michael addn. of N-acetylcysteine Me ester to acylaminoacrylates depended least on the acyl moiety. A library of 100 fragment-substituted acylaminoacrylates was prepd.; addn. of subsets of the library to papain followed by mass spectrometric anal. identified three acylaminoacrylates which selectively reacted with the cysteine protease papain. The kinetics of the inhibition of papain by the acylaminoacrylates, the effect of known inhibitors of papain on its inhibition by the acylaminoacrylates, and the lack of inhibition of other cysteine proteases (human rhinovirus 3C protease, the catalytic domain of the deubiquitinase USP08, and the E2 ubiquitin-conjugating enzyme UbcH7) by the acylaminoacrylates supported their identification as selective and irreversible papain inhibitors.(b) Kathman, S. G.; Span, I.; Smith, A. T.; Xu, Z.; Zhan, J.; Rosenzweig, A. C.; Statsyuk, A. V. A small molecule that switches a ubiquitin ligase from a processive to a distributive enzymatic mechanism. J. Am. Chem. Soc. 2015, 137, 12442– 12445, DOI: 10.1021/jacs.5b06839[ACS Full Text], [CAS], Google Scholar229bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsV2mtLvO&md5=bf3532047b8f09399e3bf6dcc87ff50dA Small Molecule That Switches a Ubiquitin Ligase From a Processive to a Distributive Enzymatic MechanismKathman, Stefan G.; Span, Ingrid; Smith, Aaron T.; Xu, Ziyang; Zhan, Jennifer; Rosenzweig, Amy C.; Statsyuk, Alexander V.Journal of the American Chemical Society (2015), 137 (39), 12442-12445CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)E3 ligases are genetically implicated in many human diseases, yet E3 enzyme mechanisms are not fully understood, and there is a strong need for pharmacol. probes of E3s. We report the discovery that the HECT E3 Nedd4-1 is a processive enzyme and that disruption of its processivity by biochem. mutations or small mols. switches Nedd4-1 from a processive to a distributive mechanism of polyubiquitin chain synthesis. Furthermore, we discovered and structurally characterized the first covalent inhibitor of Nedd4-1, which switches Nedd4-1 from a processive to a distributive mechanism. To visualize the binding mode of the Nedd4-1 inhibitor, we used X-ray crystallog. and solved the first structure of a Nedd4-1 family ligase bound to an inhibitor. Importantly, our study shows that processive Nedd4-1, but not the distributive Nedd4-1:inhibitor complex, is able to synthesize polyubiquitin chains on the substrate in the presence of the deubiquitinating enzyme USP8. Therefore, inhibition of E3 ligase processivity is a viable strategy to design E3 inhibitors. Our study provides fundamental insights into the HECT E3 mechanism and uncovers a novel class of HECT E3 inhibitors.
- 230Johansson, H.; Tsai, Y. I.; Fantom, K.; Chung, C. W.; Kümper, S.; Martino, L.; Thomas, D. A.; Eberl, H. C.; Muelbaier, M.; House, D.; Rittinger, K. Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIP. J. Am. Chem. Soc. 2019, 141, 2703, DOI: 10.1021/jacs.8b13193[ACS Full Text], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVahtrY%253D&md5=c5ca10ce463f1382a7621d28e8b7ba11Fragment-based covalent ligand screening enables rapid discovery of inhibitors for the RBR E3 ubiquitin ligase HOIPJohansson, Henrik; Isabella Tsai, Yi-Chun; Fantom, Ken; Chung, Chun-Wa; Kumper, Sandra; Martino, Luigi; Thomas, Daniel A.; Eberl, H. Christian; Muelbaier, Marcel; House, David; Rittinger, KatrinJournal of the American Chemical Society (2019), 141 (6), 2703-2712CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Modification of proteins with polyubiquitin chains is a key regulatory mechanism to control cellular behavior and alterations in the ubiquitin system are linked to many diseases. Linear (M1-linked) polyubiquitin chains play pivotal roles in several cellular signaling pathways mediating immune and inflammatory responses and apoptotic cell death. These chains are formed by the linear ubiquitin chain assembly complex (LUBAC), a multiprotein E3 ligase that consists of 3 subunits, HOIP, HOIL-1L, and SHARPIN. Herein, we describe the discovery of inhibitors targeting the active site cysteine of the catalytic subunit HOIP using fragment-based covalent ligand screening. We report the synthesis of a diverse library of electrophilic fragments and demonstrate an integrated use of protein LC-MS, biochem. ubiquitination assays, chem. synthesis, and protein crystallog. to enable the first structure-based development of covalent inhibitors for an RBR E3 ligase. Furthermore, using cell-based assays and chemoproteomics, we demonstrate that these compds. effectively penetrate mammalian cells to label and inhibit HOIP and NF-κB activation, making them suitable hits for the development of selective probes to study LUBAC biol. Our results illustrate the power of fragment-based covalent ligand screening to discover lead compds. for challenging targets, which holds promise to be a general approach for the development of cell-permeable inhibitors of thioester-forming E3 ubiquitin ligases.
- 231Lavogina, D.; Lust, M.; Viil, I.; König, N.; Raidaru, G.; Rogozina, J.; Enkvist, E.; Uri, A.; Bossemeyer, D. Structural analysis of ARC-type inhibitor (ARC-1034) binding to protein kinase A catalytic subunit and rational design of bisubstrate analogue inhibitors of basophilic protein kinases. J. Med. Chem. 2009, 52, 308– 321, DOI: 10.1021/jm800797n[ACS Full Text], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFWmug%253D%253D&md5=e50dd17444e6d94c9193ee5a91d0e0c9Structural Analysis of ARC-Type Inhibitor (ARC-1034) Binding to Protein Kinase A Catalytic Subunit and Rational Design of Bisubstrate Analogue Inhibitors of Basophilic Protein KinasesLavogina, Darja; Lust, Marje; Viil, Indrek; Konig, Norbert; Raidaru, Gerda; Rogozina, Jevgenia; Enkvist, Erki; Uri, Asko; Bossemeyer, DirkJournal of Medicinal Chemistry (2009), 52 (2), 308-321CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The crystal structure of a complex of the catalytic subunit (type α) of cAMP-dependent protein kinase (PKA Cα) with ARC-type inhibitor (ARC-1034), the presumed lead scaffold of previously reported adenosine-oligo-arginine conjugate-based (ARC-type) inhibitors, was solved. Structural elements important for interaction with the kinase were established with specifically modified derivs. of the lead compd. On the basis of this knowledge, a new generation of inhibitors, conjugates of adenosine-4'-dehydroxymethyl-4'-carboxylic acid moiety and oligo(D-arginine), was developed with inhibitory consts. well into the subnanomolar range. The structural determinants of selectivity of the new compds. were established in assays with ROCK-II and PKBγ.
- 232Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A. M.; Wright, G. D.; Auclair, K. Synthesis and structure-activity relationships of truncated bisubstrate inhibitors of aminoglycoside 6′-N-acetyltransferases. J. Med. Chem. 2006, 49, 5273– 5281, DOI: 10.1021/jm060732n[ACS Full Text], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XnsF2gsr4%253D&md5=029f6fb9997964100f1316de2e44c666Synthesis and Structure-Activity Relationships of Truncated Bisubstrate Inhibitors of Aminoglycoside 6'-N-AcetyltransferasesGao, Feng; Yan, Xuxu; Shakya, Tushar; Baettig, Oliver M.; Ait-Mohand-Brunet, Samia; Berghuis, Albert M.; Wright, Gerard D.; Auclair, KarineJournal of Medicinal Chemistry (2006), 49 (17), 5273-5281CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Truncated aminoglycoside-CoA bisubstrate analogs, e.g I, were efficiently prepd. using a convergent approach where the amine and the thiol are coupled in one-pot chemo- and regioselective coupling reaction with the addn. of a linker, without the need for protecting groups. These derivs. were tested for their effect on the activity of the resistance-causing enzyme aminoglycoside 6'-N-acetyltransferase Ii, and key structure-activity relationships are reported. Moreover, one of the inhibitors is able to block aminoglycoside resistance in cells expressing this enzyme.
- 233Bockman, M. R.; Kalinda, A. S.; Petrelli, R.; De la Mora-Rey, T.; Tiwari, D.; Liu, F.; Dawadi, S.; Nandakumar, M.; Rhee, K. Y.; Schnappinger, D.; Finzel, B. C.; Aldrich, C. C. Targeting mycobacterium tuberculosis biotin protein ligase (MtBPL) with nucleoside-based bisubstrate adenylation inhibitors. J. Med. Chem. 2015, 58, 7349– 7369, DOI: 10.1021/acs.jmedchem.5b00719[ACS Full Text], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOqu73O&md5=ff3aa92e11c9558f140837fe547c2649Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bi-substrate Adenylation InhibitorsBockman, Matthew R.; Kalinda, Alvin S.; Petrelli, Riccardo; De la Mora-Rey, Teresa; Tiwari, Divya; Liu, Feng; Dawadi, Surrendra; Nandakumar, Madhumitha; Rhee, Kyu Y.; Schnappinger, Dirk; Finzel, Barry C.; Aldrich, Courtney C.Journal of Medicinal Chemistry (2015), 58 (18), 7349-7369CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic tuberculosis (TB), remains the second leading cause of mortality among infectious diseases worldwide. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metab. through the post-translational biotinylation of acyl CoA carboxylases. We report the synthesis and evaluation of a systematic series of potent nucleoside-based inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compds. were characterized by isothermal titrn. calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Addnl., we obtained high-resoln. co-crystal structures for a majority of the compds. Despite fairly uniform biochem. potency, the whole-cell Mtb activity varied greatly with min. inhibitory concns. (MIC) ranging from 0.78 to >100 μM. Cellular accumulation studies showed a nearly 10-fold enhancement in accumulation of a C-2'-α analog over the corresponding C-2'-β analog, consistent with their differential whole-cell activity.
- 234Halby, L.; Menon, Y.; Rilova, E.; Pechalrieu, D.; Masson, V.; Faux, C.; Bouhlel, M. A.; David-Cordonnier, M. H.; Novosad, N.; Aussagues, Y.; Samson, A.; Lacroix, L.; Ausseil, F.; Fleury, L.; Guianvarc’h, D.; Ferroud, C.; Arimondo, P. B. Rational design of bisubstrate-type analogues as inhibitors of DNA methyltransferases in cancer cells. J. Med. Chem. 2017, 60, 4665– 4679, DOI: 10.1021/acs.jmedchem.7b00176[ACS Full Text], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVGgtLY%253D&md5=91cf15839ca568c0f64987ff079df5e5Rational Design of Bisubstrate-Type Analogues as Inhibitors of DNA Methyltransferases in Cancer CellsHalby, Ludovic; Menon, Yoann; Rilova, Elodie; Pechalrieu, Dany; Masson, Veronique; Faux, Celine; Bouhlel, Mohamed Amine; David-Cordonnier, Marie-Helene; Novosad, Natacha; Aussagues, Yannick; Samson, Arnaud; Lacroix, Laurent; Ausseil, Frederic; Fleury, Laurence; Guianvarc'h, Dominique; Ferroud, Clotilde; Arimondo, Paola B.Journal of Medicinal Chemistry (2017), 60 (11), 4665-4679CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Aberrant DNA hypermethylation of promoter of tumor suppressor genes is commonly obsd. in cancer and its inhibition by small mols. is promising for their reactivation. Here the authors designed bisubstrate analogs-based inhibitors, by mimicking each substrate, - the S-adenosyl-L-methionine and the deoxycytidine -, and linking them together. This approach resulted in quinazoline-quinoline derivs. as potent inhibitors of DNMT3A and DNMT1, some showing certain isoform selectivity. The authors highlighted the importance of (i) the nature and rigidity of the linker between the two moieties for inhibition, as (ii) the presence of the nitrogen on the quinoline group and (iii) of a hydrophobic group on the quinazoline. The most potent inhibitors induced demethylation of CDKN2A promoter in colon carcinoma HCT116 cells and its reactivation after 7 days of treatment. Furthermore, in a leukemia cells model system, the authors found a correlation between demethylation of the promoter induced by the treatment, chromatin opening at the promoter and the reactivation of a reporter gene.
- 235Babault, N.; Allali-Hassani, A.; Li, F.; Fan, J.; Yue, A.; Ju, K.; Liu, F.; Vedadi, M.; Liu, J.; Jin, J. Discovery of bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT). J. Med. Chem. 2018, 61, 1541– 1551, DOI: 10.1021/acs.jmedchem.7b01422[ACS Full Text], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXotVOruw%253D%253D&md5=50e23e5f60beb64c184f6eadc6a75883Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)Babault, Nicolas; Allali-Hassani, Abdellah; Li, Fengling; Fan, Jie; Yue, Alex; Ju, Kevin; Liu, Feng; Vedadi, Masoud; Liu, Jing; Jin, JianJournal of Medicinal Chemistry (2018), 61 (4), 1541-1551CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-contg. compds. using the cofactor S-5'-adenosyl-L-methionine (SAM) as the Me group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays important role in physiol. and pathophysiol. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-mol. NNMT inhibitors are valuable chem. tools for testing biol. and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6), and characterization of this inhibitor in biochem., biophys., kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-mol. inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future.
- 236Cinelli, M. A.; Li, H.; Chreifi, G.; Poulos, T. L.; Silverman, R. B. Nitrile in the hole: Discovery of a small auxiliary pocket in neuronal nitric oxide synthase leading to the development of potent and selective 2-aminoquinoline Inhibitors. J. Med. Chem. 2017, 60, 3958– 3978, DOI: 10.1021/acs.jmedchem.7b00259[ACS Full Text], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt1CgsL4%253D&md5=d28b9e3c938b76a20895b2558acef929Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline InhibitorsCinelli, Maris A.; Li, Huiying; Chreifi, Georges; Poulos, Thomas L.; Silverman, Richard B.Journal of Medicinal Chemistry (2017), 60 (9), 3958-3978CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compds. had decreased permeability, low human nNOS activity, and low selectivity vs. human eNOS. In this study, 5-substituted Ph ether-linked aminoquinolines and derivs. were synthesized and assayed against purified NOS isoforms. 5-Cyano compds. are esp. potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compds.
- 237Ye, S.; Loll, B.; Berger, A. A.; Mülow, U.; Alings, C.; Wahl, M. C.; Koksch, B. Fluorine teams up with water to restore inhibitor activity to mutant BPTI. Chem. Sci. 2015, 6, 5246– 5254, DOI: 10.1039/C4SC03227F[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVSgsbrO&md5=21a963abeae8a26436052898a6dd0edbFluorine teams up with water to restore inhibitor activity to mutant BPTIYe, Shijie; Loll, Bernhard; Berger, Allison Ann; Muelow, Ulrike; Alings, Claudia; Wahl, Markus Christian; Koksch, BeateChemical Science (2015), 6 (9), 5246-5254CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)Introducing fluorine into mols. has a wide range of effects on their physicochem. properties, often desirable but in most cases unpredictable. The fluorine atom imparts the C-F bond with low polarizability and high polarity, and significantly affects the behavior of neighboring functional groups, in a covalent or noncovalent manner. Here, we report that fluorine, present in the form of a single fluoroalkyl amino acid side chain in the P1 position of the well-characterized serine-protease inhibitor BPTI, can fully restore inhibitor activity to a mutant that contains the corresponding hydrocarbon side chain at the same site. High resoln. crystal structures were obtained for four BPTI variants in complex with bovine β-trypsin, revealing changes in the stoichiometry and dynamics of water mols. in the S1 subsite. These results demonstrate that the introduction of fluorine into a protein environment can result in "chem. complementation" that has a significantly favorable impact on protein-protein interactions.
- 238Seo, J.; Igarashi, J.; Li, H.; Martasek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water. J. Med. Chem. 2007, 50, 2089– 2099, DOI: 10.1021/jm061305c[ACS Full Text], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXktVyhur8%253D&md5=0a804fb557c4b7f81b9153e0f68e0cc0Structure-based design and synthesis of Nω-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric Oxide synthase. Displacement of the heme structural waterSeo, Jiwon; Igarashi, Jotato; Li, Huiying; Martasek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.Journal of Medicinal Chemistry (2007), 50 (9), 2089-2099CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the prodn. of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (I) (R1 = H) and (II) (R2 = H), led to the discovery of a conserved structural water mol. that was hydrogen bonded between the two heme propionates and the inhibitors. On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of II (R2 = H) or to the secondary amine nitrogen of I (R1 = H), the inhibitor mols. could displace the structural water mol. and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogs I (R1 = OH, NH2) and II (R2 = OH) which have either an N-hydroxyl or N-amino donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors I (R1 = OH) and II (R2 = OH) bound verified that the N-hydroxyl group had, indeed, displaced the structural water mol. and provided a direct interaction with the heme propionate moiety. Surprisingly, in vitro activity assay results indicated that the addn. of a hydroxyl group I (R1 = OH) only increased the potency slightly against the neuronal isoform over the parent compd. I (R1 = H). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.
- 239Fornabaio, M.; Spyrakis, F.; Mozzarelli, A.; Cozzini, P.; Abraham, D. J.; Kellogg, G. E. Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. J. Med. Chem. 2004, 47, 4507– 4516, DOI: 10.1021/jm030596b[ACS Full Text], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXmtVeitbY%253D&md5=490841fb8fea47e37d57b4bd0b530fd3Simple, Intuitive Calculations of Free Energy of Binding for Protein-Ligand Complexes. 3. The Free Energy Contribution of Structural Water Molecules in HIV-1 Protease ComplexesFornabaio, Micaela; Spyrakis, Francesca; Mozzarelli, Andrea; Cozzini, Pietro; Abraham, Donald J.; Kellogg, Glen E.Journal of Medicinal Chemistry (2004), 47 (18), 4507-4516CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural water mols. within protein active sites are relevant for ligand-protein recognition because they modify the active site geometry and contribute to binding affinity. An anal. of the interactions between 23 ligands and dimeric HIV-1 protease is reported. The x-ray structures of these complexes show the presence of four types of structural water mols.: water 301 (on the symmetry axis), water 313, water 313bis, and peripheral waters. Except for water 301, these are generally complemented with a symmetry-related set. The GRID program was used both for checking water locations and for placing water mols. that appear to be missing from the complexes due to crystallog. uncertainty. Hydropathic anal. of the energetic contributions using HINT indicates a significant improvement of the correlation between HINT scores and the exptl. detd. binding consts. when the appropriate bridging water mols. are taken into account. In the absence of water r2 = 0.30 with a std. error of ± 1.30 kcal mol-1 and when the energetic contributions of the constrained waters are included r2 = 0.61 with a std. error of ± 0.98 kcal mol-1. HINT was shown to be able to map quant. the contribution of individual structural waters to binding energy. The order of relevance for the various types of water is water 301 > water 313 > water 313bis > peripheral waters. Thus, to obtain the most reliable free energy predictions, the contributions of structural water mols. should be included. However, care must be taken to include the effects of water mols. that add information value and not just noise.
- 240(a) Chong, P. Y.; Shotwell, J. B.; Miller, J. F.; Price, D. J.; Maynard, A.; Voitenleitner, C.; Mathis, A.; Williams, S.; Pouliot, J.; Creech, K.; Wang, F.; Fang, J. M.; Zhang, H.; Tai, V.; Turner, E.; Kahler, K. M.; Crosby, R.; Peat, A. J. Design of N-benzoxaborole benzofuran GSK8175 - Optimization of human PK inspired by metabolites of a failed clinical HCV inhibitor. J. Med. Chem. 2019, 62, 3254, DOI: 10.1021/acs.jmedchem.8b01719[ACS Full Text.], [CAS], Google Scholar240ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtFCrsL8%253D&md5=3c8cbff5f4273f2cf43da3ec14e93f2cDesign of N-Benzoxaborole Benzofuran GSK8175-Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV InhibitorChong, Pek Y.; Shotwell, J. Brad; Miller, John; Price, Daniel J.; Maynard, Andy; Voitenleitner, Christian; Mathis, Amanda; Williams, Shawn; Pouliot, Jeffrey J.; Creech, Katrina; Wang, Feng; Fang, Jing; Zhang, Huichang; Tai, Vincent W.-F.; Turner, Elizabeth; Kahler, Kirsten M.; Crosby, Renae; Peat, Andrew J.Journal of Medicinal Chemistry (2019), 62 (7), 3254-3267CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor of hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidn. resulted in a short plasma half-life (5 h) in human volunteers, and a backup program was initiated to remove metabolic liabilities assocd. with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), a sulfonamide-N-benzoxaborole analog with low in vivo clearance across preclin. species and broad-spectrum activity against HCV replicons. An X-ray structure of NS5B protein cocrystd. with 49 revealed unique protein-inhibitor interactions mediated by an extensive network of ordered water mols. and the first evidence of boronate complex formation within the binding pocket. In clin. studies, 49 displayed a 60-63 h half-life and a robust decrease in viral RNA levels in HCV-infected patients, thereby validating our hypothesis that reducing benzylic oxidn. would improve human pharmacokinetics and lower efficacious doses relative to 1.(b) Zhan, P.; Kang, D.; Liu, X. Resurrecting the condemned: Identification of N-benzoxaborole benzofuran GSK8175 as a clinical candidate with reduced metabolic liability. J. Med. Chem. 2019, 62, 3251, DOI: 10.1021/acs.jmedchem.9b00415[ACS Full Text], [CAS], Google Scholar240bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVGqtbg%253D&md5=5e49c814c668f48322097841bb1f593bResurrecting the condemned: identification of N-benzoxaborole benzofuran GSK8175 as a clinical candidate with reduced metabolic liabilityZhan, Peng; Kang, Dongwei; Liu, XinyongJournal of Medicinal Chemistry (2019), 62 (7), 3251-3253CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Recently, in a program designed to improve the metabolic stability of the HCV inhibitor GSK5852, N-benzoxaborole benzofuran (GSK8175) emerged as a clin. candidate that not only retains the broad-spectrum activity against HCV subgenomic replicons but is free of the N-benzylboronic acid structure, which is a metabolic liability, and probably the cause of low in vivo clearance in preclin. species. This Viewpoint discusses some medicinal chem. issues involved in the identification of GSK8175.
- 241Spyrakis, F.; Ahmed, M. H.; Bayden, A. S.; Cozzini, P.; Mozzarelli, A.; Kellogg, G. E. The roles of water in the protein matrix: a largely untapped resource for drug discovery. J. Med. Chem. 2017, 60, 6781– 6827, DOI: 10.1021/acs.jmedchem.7b00057[ACS Full Text], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXntVyru7s%253D&md5=1e6f76629bf2eeabf8b491f8814cfc69The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug DiscoverySpyrakis, Francesca; Ahmed, Mostafa H.; Bayden, Alexander S.; Cozzini, Pietro; Mozzarelli, Andrea; Kellogg, Glen E.Journal of Medicinal Chemistry (2017), 60 (16), 6781-6827CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The value of thoroughly understanding the thermodn. specific to a drug discovery/design study is well known. Over the past decade, the crucial roles of water mols. in protein structure, function, and dynamics have also become increasingly appreciated. This Perspective explores water in the biol. environment by adopting its point of view in such phenomena. The prevailing thermodn. models of the past, where water was seen largely in terms of an entropic gain after its displacement by a ligand, are now known to be much too simplistic. We adopt a set of terminol. that describes water mols. as being "hot" and "cold", which we have defined as being easy and difficult to displace, resp. The basis of these designations, which involve both enthalpic and entropic water contributions, are explored in several classes of biomols. and structural motifs. The hallmarks for characterizing water mols. are examd., and computational tools for evaluating water-centric thermodn. are reviewed. This Perspective's summary features guidelines for exploiting water mols. in drug discovery.
- 242Gerstenberger, B. S.; Trzupek, J. D.; Tallant, C.; Fedorov, O.; Filippakopoulos, P.; Brennan, P. E.; Fedele, V.; Martin, S.; Picaud, S.; Rogers, C.; Parikh, M.; Taylor, A.; Samas, B.; O’Mahony, A.; Berg, E.; Pallares, G.; Torrey, A. D.; Treiber, D. K.; Samardjiev, I. J.; Nasipak, B. T.; Padilla-Benavides, T.; Wu, Q.; Imbalzano, A. N.; Nickerson, J. A.; Bunnage, M. E.; Muller, S.; Knapp, S.; Owen, D. R. Identification of a chemical probe for family VIII bromodomains through optimization of a fragment hit. J. Med. Chem. 2016, 59, 4800– 4811, DOI: 10.1021/acs.jmedchem.6b00012[ACS Full Text], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xmsl2rs74%253D&md5=6cb73e76a19f7fb44153f8cbfeff9cf6Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment HitGerstenberger, Brian S.; Trzupek, John D.; Tallant, Cynthia; Fedorov, Oleg; Filippakopoulos, Panagis; Brennan, Paul E.; Fedele, Vita; Martin, Sarah; Picaud, Sarah; Rogers, Catherine; Parikh, Mihir; Taylor, Alexandria; Samas, Brian; O'Mahony, Alison; Berg, Ellen; Pallares, Gabriel; Torrey, Adam V.; Treiber, Daniel K.; Samardjiev, Ivan J.; Nasipak, Brian T.; Padilla-Benavides, Teresita; Wu, Qiong; Imbalzano, Anthony N.; Nickerson, Jeffrey A.; Bunnage, Mark E.; Muller, Susanne; Knapp, Stefan; Owen, Dafydd R.Journal of Medicinal Chemistry (2016), 59 (10), 4800-4811CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water mols. that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chem. program that led to PFI-3 from an initial fragment screening hit is described in detail, and addnl. analogs with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacol. characterization of PFI-3 as a chem. probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.
- 243Kuhne, S.; Kooistra, A. J.; Bosma, R.; Bortolato, A.; Wijtmans, M.; Vischer, H. F.; Mason, J. S.; de Graaf, C.; de Esch, I. J.; Leurs, R. Identification of ligand binding hot spots of the histamine H1 receptor following structure-based fragment optimization. J. Med. Chem. 2016, 59, 9047– 9061, DOI: 10.1021/acs.jmedchem.6b00981[ACS Full Text], [CAS], Google Scholar243https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFanu7rK&md5=7e9bd27144fcaf11a3176bf717849bcdIdentification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment OptimizationKuhne, Sebastiaan; Kooistra, Albert J.; Bosma, Reggie; Bortolato, Andrea; Wijtmans, Maikel; Vischer, Henry F.; Mason, Jonathan S.; de Graaf, Chris; de Esch, Iwan J. P.; Leurs, RobJournal of Medicinal Chemistry (2016), 59 (19), 9047-9061CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Developments in G protein-coupled receptor (GPCR) structural biol. provide insights into GPCR-ligand binding. Compd. I (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivs. to investigate the roles of: (1) the amine-binding region, (2) the upper and lower arom. region and (3) binding site solvation. SAR anal. showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water mol. from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of I. Deconstruction of I showed that the lower arom. region serves as a secondary binding hot spot. This study demonstrates that an x-ray structure in combination with tool compds., assessment of water energetics, and mutagenesis studies enables SAR exploration to map GPCR-ligand binding hot spots.
- 244Blanco, B.; Sedes, A.; Peon, A.; Otero, J. M.; van Raaij, M. J.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Exploring the water-binding pocket of the type II dehydroquinase enzyme in the structure-based design of inhibitors. J. Med. Chem. 2014, 57, 3494– 3510, DOI: 10.1021/jm500175z[ACS Full Text], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXltF2ku7Y%253D&md5=06d1c7306e1937956f3a6420bbab16f3Exploring the water-binding pocket of the type II dehydroquinase enzyme in the structure-based design of inhibitorsBlanco, Beatriz; Sedes, Antia; Peon, Antonio; Otero, Jose M.; van Raaij, Mark J.; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2014), 57 (8), 3494-3510CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Structural and computational studies to explore the WAT1 binding pocket in the structure-based design of inhibitors against the type II dehydroquinase (DHQ2) enzyme are reported. The crystal structures of DHQ2 from M. tuberculosis in complex with four of the reported compds. are described. The electrostatic interaction obsd. between the guanidinium group of the essential arginine and the carboxylate group of one of the inhibitors in the reported crystal structures supports the recently suggested role of this arginine as the residue that triggers the release of the product from the active site. The results of the structural and mol. dynamics simulation studies revealed that the inhibitory potency is favored by promoting interactions with WAT1 and the residues located within this pocket and, more importantly, by avoiding situations where the ligands occupy the WAT1 binding pocket. The new insights can be used to advantage in the structure-based design of inhibitors.
- 245Wright, Z. V. F.; Wu, N. C.; Kadam, R. U.; Wilson, I. A.; Wolan, D. W. Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin. Bioorg. Med. Chem. Lett. 2017, 27, 3744– 3748, DOI: 10.1016/j.bmcl.2017.06.074[Crossref], [PubMed], [CAS], Google Scholar245https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFCgtbvK&md5=036be03e9d7f3959120c772fa87f2317Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutininWright, Zoe V. F.; Wu, Nicholas C.; Kadam, Rameshwar U.; Wilson, Ian A.; Wolan, Dennis W.Bioorganic & Medicinal Chemistry Letters (2017), 27 (16), 3744-3748CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We detd. the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compds. Addn. of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water mol. in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogs represent novel leads to yield more potent compds. against hemagglutinin that block viral entry.
- 246Mosure, S.; Shang, J.; Eberhardt, J.; Brust, R.; Zheng, J.; Griffin, P. R.; Forli, S.; Kojetin, D. J. Structural basis of altered potency and efficacy displayed by a major in vivo metabolite of the anti-diabetic PPARγ drug pioglitazone. J. Med. Chem. 2019, 62, 2008, DOI: 10.1021/acs.jmedchem.8b01573[ACS Full Text], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFSjt78%253D&md5=8986f54f42e74d9714b9e31826b52e7bStructural basis of altered potency and efficacy displayed by a major in vivo metabolite of the Antidiabetic PPARγ drug pioglitazoneMosure, Sarah A.; Shang, Jinsai; Eberhardt, Jerome; Brust, Richard; Zheng, Jie; Griffin, Patrick R.; Forli, Stefano; Kojetin, Douglas J.Journal of Medicinal Chemistry (2019), 62 (4), 2008-2023CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Pioglitazone (Pio) is a Food and Drug Administration-approved drug for type-2 diabetes that binds and activates the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), yet it remains unclear how in vivo Pio metabolites affect PPARγ structure and function. Here, we present a structure-function comparison of Pio and its most abundant in vivo metabolite, 1-hydroxypioglitazone (PioOH). PioOH displayed a lower binding affinity and reduced potency in co-regulator recruitment assays. X-ray crystallog. and mol. docking anal. of PioOH-bound PPARγ ligand-binding domain revealed an altered hydrogen bonding network, including the formation of water-mediated bonds, which could underlie its altered biochem. phenotype. NMR spectroscopy and hydrogen/deuterium exchange mass spectrometry anal. coupled to activity assays revealed that PioOH better stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and better enhances co-activator binding, affording slightly better transcriptional efficacy. These results indicating that Pio hydroxylation affects its potency and efficacy as a PPARγ agonist contributes to our understanding of PPARγ-drug metabolite interactions.
- 247Thomaston, J. L.; Polizzi, N. F.; Konstantinidi, A.; Wang, J.; Kolocouris, A.; DeGrado, W. F. Inhibitors of the M2 proton channel engage and disrupt transmembrane networks of hydrogen-bonded waters. J. Am. Chem. Soc. 2018, 140, 15219, DOI: 10.1021/jacs.8b06741[ACS Full Text], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1ensLfK&md5=5d6f01de165142f3494bc4f12a8ced9aInhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded WatersThomaston, Jessica L.; Polizzi, Nicholas F.; Konstantinidi, Athina; Wang, Jun; Kolocouris, Antonios; DeGrado, William F.Journal of the American Chemical Society (2018), 140 (45), 15219-15226CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-mol. approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small mols. can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using x-ray crystallog. have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resoln. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. These drug-bound complexes provide the first high-resoln. structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.
- 248Geist, L.; Mayer, M.; Cockcroft, X.-L.; Wolkerstorfer, B.; Kessler, D.; Engelhardt, H.; McConnell, D. B.; Konrat, R. Direct NMR probing of hydration shells of protein ligand interfaces and its application to drug design. J. Med. Chem. 2017, 60, 8708– 8715, DOI: 10.1021/acs.jmedchem.7b00845[ACS Full Text], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsV2js7%252FJ&md5=36b9cb69d63d216eedaa081d3d2605b8Direct NMR Probing of Hydration Shells of Protein Ligand Interfaces and Its Application to Drug DesignGeist, Leonhard; Mayer, Moriz; Cockcroft, Xiao-Ling; Wolkerstorfer, Bernhard; Kessler, Dirk; Engelhardt, Harald; McConnell, Darryl B.; Konrat, RobertJournal of Medicinal Chemistry (2017), 60 (21), 8708-8715CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Fragment-based drug design exploits initial screening of low mol. wt. compds. and their concomitant affinity improvement. The multitude of possible chem. modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodol. (LOGSY titrn.) that allows the detn. of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addn. of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodol. and in contrast to conventional ligand-based methods is the independence of the mol. wt. of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain contg. protein 4, a prominent cancer target in pharmaceutical industry.
- 249Murphy, R. B.; Repasky, M. P.; Greenwood, J. R.; Tubert-Brohman, I.; Jerome, S.; Annabhimoju, R.; Boyles, N. A.; Schmitz, C. D.; Abel, R.; Farid, R.; Friesner, R. A. WScore: A flexible and accurate treatment of explicit water molecules in ligand-receptor docking. J. Med. Chem. 2016, 59, 4364– 4384, DOI: 10.1021/acs.jmedchem.6b00131[ACS Full Text], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xls1Gqtr4%253D&md5=dcb2bc320a1bffe608531c4aa01666bbWScore: A Flexible and Accurate Treatment of Explicit Water Molecules in Ligand-Receptor DockingMurphy, Robert B.; Repasky, Matthew P.; Greenwood, Jeremy R.; Tubert-Brohman, Ivan; Jerome, Steven; Annabhimoju, Ramakrishna; Boyles, Nicholas A.; Schmitz, Christopher D.; Abel, Robert; Farid, Ramy; Friesner, Richard A.Journal of Medicinal Chemistry (2016), 59 (9), 4364-4384CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We have developed a new methodol. for protein-ligand docking and scoring, WScore, incorporating a flexible description of explicit water mols. The locations and thermodn. of the waters are derived from a WaterMap mol. dynamics simulation. The water structure is employed to provide an at. level description of ligand and protein desolvation. WScore also contains a detailed model for localized ligand and protein strain energy and integrates an MM-GBSA scoring component with these terms to assess delocalized strain of the complex. Ensemble docking is used to take into account induced fit effects on the receptor conformation, and protein reorganization free energies are assigned via fitting to exptl. data. The performance of the method is evaluated for pose prediction, rank ordering of self-docked complexes, and enrichment in virtual screening, using a large data set of PDB complexes and compared with the Glide SP and Glide XP models; significant improvements are obtained.
- 250Peach, M. L.; Tan, N.; Choyke, S. J.; Giubellino, A.; Athauda, G.; Burke, T. R., Jr.; Nicklaus, M. C.; Bottaro, D. P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem. 2009, 52, 943– 951, DOI: 10.1021/jm800791f[ACS Full Text], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtFGrsw%253D%253D&md5=1b814fef6ce3ceb055f899379fdb8d8cDirected Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual ScreeningPeach, Megan L.; Tan, Nelly; Choyke, Sarah J.; Giubellino, Alessio; Athauda, Gagani; Burke, Terrence R., Jr.; Nicklaus, Marc C.; Bottaro, Donald P.Journal of Medicinal Chemistry (2009), 52 (4), 943-951CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Hepatocyte growth factor (HGF) is an important regulator of normal development and homeostasis, and dysregulated signaling through the HGF receptor, Met, contributes to tumorigenesis, tumor progression, and metastasis in numerous human malignancies. The development of selective small-mol. inhibitors of oncogenic tyrosine kinases (TK) has led to well-tolerated, targeted therapies for a growing no. of cancer types. To identify selective Met TK inhibitors, we used a high-throughput virtual screen of the 13.5 million compd. ChemNavigator database to find compds. most likely to bind to the Met ATP binding site and to form several crit. interactions with binding site residues predicted to stabilize the kinase domain in its inactive conformation. Subsequent biol. screening of 70 in silico hit structures using cell-free and intact cell assays identified three active compds. with micromolar IC50 values. The predicted binding modes and target selectivity of these compds. are discussed and compared to other known Met TK inhibitors.
- 251Klüter, S.; Grutter, C.; Naqvi, T.; Rabiller, M.; Simard, J. R.; Pawar, V.; Getlik, M.; Rauh, D. Displacement assay for the detection of stabilizers of inactive kinase conformations. J. Med. Chem. 2010, 53, 357– 367, DOI: 10.1021/jm901297e[ACS Full Text], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhsVKhs7fO&md5=4bee62eba370bd4b7c40ba5ab6bd2be2Displacement Assay for the Detection of Stabilizers of Inactive Kinase ConformationsKlueter, Sabine; Gruetter, Christian; Naqvi, Tabassum; Rabiller, Matthias; Simard, Jeffrey R.; Pawar, Vijaykumar; Getlik, Matthaeus; Rauh, DanielJournal of Medicinal Chemistry (2010), 53 (1), 357-367CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Targeting protein kinases with small mols. outside the highly conserved ATP pocket to stabilize inactive kinase conformations is becoming a more desirable approach in kinase inhibitor research, since these mols. have advanced pharmacol. properties compared to compds. exclusively targeting the ATP pocket. Traditional screening approaches for kinase inhibitors are often based on enzyme activity, but they may miss inhibitors that stabilize inactive kinase conformations by enriching the active state of the kinase. Here we present the development of a kinase binding assay employing a pyrazolourea type III inhibitor and enzyme fragment complementation (EFC) technol. that is suitable to screen stabilizers of enzymically inactive kinases. To validate this assay system, we report the binding characteristics of a series of kinase inhibitors to inactive p38α and JNK2. Addnl., we present protein X-ray crystallog. studies to examine the binding modes of potent quinoline-based DFG-out binders in p38α.
- 252(a) Whelligan, D. K.; Solanki, S.; Taylor, D.; Thomson, D. W.; Cheung, K. M.; Boxall, K.; Mas-Droux, C.; Barillari, C.; Burns, S.; Grummitt, C. G.; Collins, I.; van Montfort, R. L.; Aherne, G. W.; Bayliss, R.; Hoelder, S. Aminopyrazine inhibitors binding to an unusual inactive conformation of the mitotic kinase Nek2: SAR and structural characterization. J. Med. Chem. 2010, 53, 7682– 7698, DOI: 10.1021/jm1008727[ACS Full Text.], [CAS], Google Scholar252ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Krs7nI&md5=d1a4af6869319bed0a340e8ff7db4397Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural CharacterizationWhelligan, Daniel K.; Solanki, Savade; Taylor, Dawn; Thomson, Douglas W.; Cheung, Kwai-Ming J.; Boxall, Kathy; Mas-Droux, Corine; Barillari, Caterina; Burns, Samantha; Grummitt, Charles G.; Collins, Ian; van Montfort, Rob L. M.; Aherne, G. Wynne; Bayliss, Richard; Hoelder, SwenJournal of Medicinal Chemistry (2010), 53 (21), 7682-7698CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine I, compds. with improved activity were identified using structure-based design. Our structural biol. investigations reveal two notable observations. First, I and related compds. bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.(b) Colombano, G.; Caldwell, J. J.; Matthews, T. P.; Bhatia, C.; Joshi, A.; McHardy, T.; Mok, N. Y.; Newbatt, Y.; Pickard, L.; Strover, J.; Hedayat, S.; Walton, M. I.; Myers, S.; Jones, A. M.; Saville, H.; McAndrew, C.; Burke, R.; Eccles, S.; Davies, F.; Bayliss, R.; Collins, I. Binding to an unusual inactive kinase conformation by highly selective inhibitors of inositol-requiring enzyme 1α kinase-endoribonuclease. J. Med. Chem. 2019, 62, 2447, DOI: 10.1021/acs.jmedchem.8b01721[ACS Full Text], [CAS], Google Scholar252bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXjtlSqsr8%253D&md5=9e4f266c35c4c4ec08e72f753b4f58a6Binding to an Unusual Inactive Kinase Conformation by Highly Selective Inhibitors of Inositol-Requiring Enzyme 1α Kinase-EndoribonucleaseColombano, Giampiero; Caldwell, John J.; Matthews, Thomas P.; Bhatia, Chitra; Joshi, Amar; McHardy, Tatiana; Mok, Ngai Yi; Newbatt, Yvette; Pickard, Lisa; Strover, Jade; Hedayat, Somaieh; Walton, Michael I.; Myers, Stephanie M.; Jones, Alan M.; Saville, Harry; McAndrew, Craig; Burke, Rosemary; Eccles, Suzanne A.; Davies, Faith E.; Bayliss, Richard; Collins, IanJournal of Medicinal Chemistry (2019), 62 (5), 2447-2465CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A series of imidazo[1,2-b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compds. with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallog. showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.
- 253Prado, V.; Lence, E.; Maneiro, M.; Vazquez-Ucha, J. C.; Beceiro, A.; Thompson, P.; Hawkins, A. R.; Gonzalez-Bello, C. Targeting the motion of shikimate kinase: development of competitive inhibitors that stabilize an inactive open conformation of the enzyme. J. Med. Chem. 2016, 59, 5471– 5487, DOI: 10.1021/acs.jmedchem.6b00483[ACS Full Text], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnslWiurY%253D&md5=9022076b2c4efd51c65322374dfb7ed7Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the EnzymePrado, Veronica; Lence, Emilio; Maneiro, Maria; Vazquez-Ucha, Juan C.; Beceiro, Alejandro; Thompson, Paul; Hawkins, Alastair R.; Gonzalez-Bello, ConcepcionJournal of Medicinal Chemistry (2016), 59 (11), 5471-5487CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The large conformational changes obsd. by Mol. Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogs interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivs. 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient deriv. in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.
- 254Weisner, J.; Gontla, R.; van der Westhuizen, L.; Oeck, S.; Ketzer, J.; Janning, P.; Richters, A.; Mühlenberg, T.; Fang, Z.; Taher, A.; Jendrossek, V.; Pelly, S. C.; Bauer, S.; van Otterlo, W. A.; Rauh, D. Covalent-allosteric kinase inhibitors. Angew. Chem., Int. Ed. 2015, 54, 10313– 10316, DOI: 10.1002/anie.201502142[Crossref], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKms7fE&md5=9502910ef46da0e7e7ae7d2156e0a292Covalent-Allosteric Kinase InhibitorsWeisner, Joern; Gontla, Rajesh; van der Westhuizen, Leandi; Oeck, Sebastian; Ketzer, Julia; Janning, Petra; Richters, Andre; Muehlenberg, Thomas; Fang, Zhizhou; Taher, Abu; Jendrossek, Verena; Pelly, Stephen C.; Bauer, Sebastian; van Otterlo, Willem A. L.; Rauh, DanielAngewandte Chemie, International Edition (2015), 54 (35), 10313-10316CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homol. (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chem. biol. and medicinal chem. research.
- 255(a) Milroy, L. G.; Bartel, M.; Henen, M. A.; Leysen, S.; Adriaans, J. M.; Brunsveld, L.; Landrieu, I.; Ottmann, C. Stabilizer-guided inhibition of protein-protein interactions. Angew. Chem., Int. Ed. 2015, 54, 15720– 15724, DOI: 10.1002/anie.201507976[Crossref], [CAS], Google Scholar.255ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyht7%252FP&md5=e2db0e3b3f9a155f5ce739e8c7cc6875Stabilizer-Guided Inhibition of Protein-Protein InteractionsMilroy, Lech-Gustav; Bartel, Maria; Henen, Morkos A.; Leysen, Seppe; Adriaans, Joris M. C.; Brunsveld, Luc; Landrieu, Isabelle; Ottmann, ChristianAngewandte Chemie, International Edition (2015), 54 (52), 15720-15724CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The discovery of novel protein-protein interaction (PPI) modulators represents one of the great mol. challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compds., which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, the authors combine x-ray crystallog. data from both stabilizer and inhibitor co-crystal complexes of the adapter protein 14-3-3 to characterize, down to the at. scale, inhibitors of the 14-3-3/Tau PPI, a potential drug target to treat Alzheimer's disease. The most potent compd. notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. The authors' work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14-3-3 and other PPIs.(b) Sijbesma, E.; Hallenbeck, K. K.; Leysen, S.; de Vink, P.; Skora, L.; Jahnke, W.; Brunsveld, L.; Arkin, M. R.; Ottmann, C. Site-directed fragment-based screening for the discovery of protein-protein interaction stabilizers. J. Am. Chem. Soc. 2019, 141, 3524, DOI: 10.1021/jacs.8b11658[ACS Full Text.], [CAS], Google Scholar255bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVWjtrY%253D&md5=5e68f397675437fffdca4cc47ed8e078Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction StabilizersSijbesma, Eline; Hallenbeck, Kenneth K.; Leysen, Seppe; de Vink, Pim J.; Skora, Lukasz; Jahnke, Wolfgang; Brunsveld, Luc; Arkin, Michelle R.; Ottmann, ChristianJournal of the American Chemical Society (2019), 141 (8), 3524-3531CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Modulation of protein-protein interactions (PPIs) by small mols. has emerged as a valuable approach in drug discovery. Compared to direct inhibition, PPI stabilization is vastly underexplored but has strong advantages, including the ability to gain selectivity by targeting an interface formed only upon assocn. of proteins. Here, we present the application of a site-directed screening technique based on disulfide trapping (tethering) to select for fragments that enhance the affinity between protein partners. We target the phosphorylation-dependent interaction between the hub protein 14-3-3σ and a peptide derived from Estrogen Receptor α (ERα), an important breast cancer target that is neg. regulated by 14-3-3σ. We identify orthosteric stabilizers that increase 14-3-3/ERα affinity up to 40-fold and propose the mechanism of stabilization based on X-ray crystal structures. These fragments already display partial selectivity toward ERα-like motifs over other representative 14-3-3 clients. This first of its kind study illustrates the potential of the tethering approach to overcome the hurdles in systematic PPI stabilizer discovery.(c) Andrei, S. A.; de Vink, P.; Sijbesma, E.; Han, L.; Brunsveld, L.; Kato, N.; Ottmann, C.; Higuchi, Y. Rationally designed semisynthetic natural product analogues for stabilization of 14–3-3 protein-protein interactions. Angew. Chem., Int. Ed. 2018, 57, 13470– 13474, DOI: 10.1002/anie.201806584[Crossref], [CAS], Google Scholar255chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslahsL%252FO&md5=c168fae0a4306a739bd4681cb712b701Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14-3-3 Protein-Protein InteractionsAndrei, Sebastian A.; de Vink, Pim; Sijbesma, Eline; Han, Ling; Brunsveld, Luc; Kato, Nobuo; Ottmann, Christian; Higuchi, YusukeAngewandte Chemie, International Edition (2018), 57 (41), 13470-13474CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)The natural product family of fusicoccanes are stabilizers of 14-3-3 mediated protein-protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of mol. dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X-ray crystallog. confirmed the power of the MD-based design approach, revealing the potential for an addnl. hydrogen bond with the 14-3-3 protein to lead to significantly increased potency. Addnl., these compds. exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small-mol. PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compds., as well as allowing the study of the fundamental principles behind PPI stabilization.
- 256(a) Andrei, S. A.; Sijbesma, E.; Hann, M.; Davis, J.; O’Mahony, G.; Perry, M. W. D.; Karawajczyk, A.; Eickhoff, J.; Brunsveld, L.; Doveston, R. G.; Milroy, L. G.; Ottmann, C. Stabilization of protein-protein interactions in drug discovery. Expert Opin. Drug Discovery 2017, 12, 925– 940, DOI: 10.1080/17460441.2017.1346608[Crossref], [PubMed], [CAS], Google Scholar.256ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFOrsbnK&md5=fd6aa91fbca0e69af4a4bdb2f9ce850cStabilization of protein-protein interactions in drug discoveryAndrei, Sebastian A.; Sijbesma, Eline; Hann, Michael; Davis, Jeremy; O'Mahony, Gavin; Perry, Matthew W. D.; Karawajczyk, Anna; Eickhoff, Jan; Brunsveld, Luc; Doveston, Richard G.; Milroy, Lech-Gustav; Ottmann, ChristianExpert Opinion on Drug Discovery (2017), 12 (9), 925-940CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.): PPIs are involved in every disease and specific modulation of these PPIs with small mols. would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-mol. stabilizers of PPIs is underrepresented in drug discovery.: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a no. of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic mols. originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing no. of synthetic small-mol. PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach.: Both the natural products and the growing no. of synthetic mols. show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compd. libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of mols. reviewed here in our opinion justify these efforts.(b) Bier, D.; Thiel, P.; Briels, J.; Ottmann, C. Stabilization of protein-protein interactions in chemical biology and drug discovery. Prog. Biophys. Mol. Biol. 2015, 119, 10– 19, DOI: 10.1016/j.pbiomolbio.2015.05.002[Crossref], [PubMed], [CAS], Google Scholar.256bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVKmsb3F&md5=8a51dfc8088641b0bfa658250cd6117aStabilization of Protein-Protein Interactions in chemical biology and drug discoveryBier, David; Thiel, Philipp; Briels, Jeroen; Ottmann, ChristianProgress in Biophysics & Molecular Biology (2015), 119 (1), 10-19CODEN: PBIMAC; ISSN:0079-6107. (Elsevier Ltd.)A review. More than 300,000 Protein-Protein Interactions (PPIs) can be found in human cells. This no. is significantly larger than the no. of single proteins, which are the classical targets for pharmacol. intervention. Hence, specific and potent modulation of PPIs by small, drug-like mols. would tremendously enlarge the "druggable genome" enabling novel ways of drug discovery for essentially every human disease. This strategy is esp. promising in diseases with difficult targets like intrinsically disordered proteins or transcription factors, for example neurodegeneration or metabolic diseases. Whereas the potential of PPI modulation has been recognized in terms of the development of inhibitors that disrupt or prevent a binary protein complex, the opposite (or complementary) strategy to stabilize PPIs has not yet been realized in a systematic manner. This fact is rather surprising given the no. of impressive natural product examples that confer their activity by stabilizing specific PPIs. In addn., in recent years more and more examples of synthetic mols. are being published that work as PPI stabilizers, despite the fact that in the majority they initially have not been designed as such. Here, we describe examples from both the natural products as well as the synthetic mols. advocating for a stronger consideration of the PPI stabilization approach in chem. biol. and drug discovery.(c) Giordanetto, F.; Schäfer, A.; Ottmann, C. Stabilization of protein-protein interactions by small molecules. Drug Discovery Today 2014, 19, 1812– 1821, DOI: 10.1016/j.drudis.2014.08.005[Crossref], [PubMed], [CAS], Google Scholar.256chttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVyhtrnE&md5=1b4a81a6f84e391515f992ccb0454566Stabilization of protein-protein interactions by small moleculesGiordanetto, Fabrizio; Schaefer, Anja; Ottmann, ChristianDrug Discovery Today (2014), 19 (11), 1812-1821CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)A review. Protein-protein interactions (PPIs) are implicated in every disease and mastering the ability to influence PPIs with small mols. would considerably enlarge the druggable genome. Whereas inhibition of PPIs has repeatedly been shown to work successfully, targeted stabilization of PPIs is underrepresented in the literature. This is all the more surprising because natural products like FK506, rapamycin, brefeldin, forskolin and fusicoccin confer their physiol. activity by stabilizing specific PPIs. However, recently a no. of very interesting synthetic mols. have been reported from drug discovery projects that indeed achieve their desired activities by stabilizing either homo- or hetero-oligomeric complexes of their target proteins.(d) Thiel, P.; Kaiser, M.; Ottmann, C. Small-molecule stabilization of protein-protein interactions: an underestimated concept in drug discovery?. Angew. Chem., Int. Ed. 2012, 51, 2012– 2018, DOI: 10.1002/anie.201107616[Crossref], [CAS], Google Scholar256dhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhslCrsbk%253D&md5=7b08cfbf9af0b49cdf36e739c907c88aSmall-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery?Thiel, Philipp; Kaiser, Markus; Ottmann, ChristianAngewandte Chemie, International Edition (2012), 51 (9), 2012-2018CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The modulation of protein-protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clin. studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biol. contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI-stabilizing natural products have already found application as important drugs. Moreover, directed small-mol. stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs.
- 257Verteramo, M. L.; Stenström, O.; Ignjatović, M. M.; Caldararu, O.; Olsson, M. A.; Manzoni, F.; Leffler, H.; Oksanen, E.; Logan, D. T.; Nilsson, U. J.; Ryde, U.; Akke, M. Interplay between Conformational Entropy and Solvation Entropy in Protein-Ligand Binding. J. Am. Chem. Soc. 2019, 141, 2012– 2026, DOI: 10.1021/jacs.8b11099[ACS Full Text], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkslOitg%253D%253D&md5=b9656b2364586b09f0291f8c75728f6dInterplay between conformational entropy and solvation entropy in protein-ligand bindingVerteramo, Maria Luisa; Stenstroem, Olof; Ignjatovic, Majda Misini; Caldararu, Octav; Olsson, Martin A.; Manzoni, Francesco; Leffler, Hakon; Oksanen, Esko; Logan, Derek T.; Nilsson, Ulf J.; Ryde, Ulf; Akke, MikaelJournal of the American Chemical Society (2019), 141 (5), 2012-2026CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Understanding the driving forces underlying mol. recognition is of fundamental importance in chem. and biol. The challenge is to unravel the binding thermodn. into sep. contributions and to interpret these in mol. terms. Entropic contributions to the free energy of binding are particularly difficult to assess in this regard. Here, we pinpointed the mol. determinants underlying differences in ligand affinity to the carbohydrate recognition domain of galectin-3, using a combination of isothermal titrn. calorimetry, x-ray crystallog., NMR relaxation, and mol. dynamics (MD) simulations followed by conformational entropy and grid inhomogeneous solvation theory (GIST) analyses. Using a pair of diastereomeric ligands that have essentially identical chem. potential in the unbound state, we reduced the problem of dissecting the thermodn. to a comparison of the 2 protein-ligand complexes. While the free energies of binding were nearly equal for the R and S diastereomers, greater differences were obsd. for the enthalpy and entropy, which consequently exhibited compensatory behavior, ΔΔH°(R - S) = -5 ± 1 kJ/mol and -TΔΔS°(R - S) = 3 ± 1 kJ/mol. NMR relaxation expts. and MD simulations indicated that the protein in complex with the S-stereoisomer had greater conformational entropy than in the R-complex. GIST calcns. revealed addnl., but smaller, contributions from solvation entropy, again in favor of the S-complex. Thus, conformational entropy apparently dominates over solvation entropy in dictating the difference in the overall entropy of binding. This case highlights an interplay between conformational entropy and solvation entropy, pointing to both opportunities and challenges in drug design.
- 258Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.; Garbaccio, R. M.; Terrett, N. K.; Tillyer, R. D.; Truppo, M. D.; Parmee, E. R. The importance of synthetic chemistry in the pharmaceutical industry. Science 2019, 363, eaat0805, DOI: 10.1126/science.aat0805
- 259(a) Nielsen, T. E.; Schreiber, S. L. Towards the optimal screening collection: a synthesis strategy. Angew. Chem., Int. Ed. 2008, 47, 48– 56, DOI: 10.1002/anie.200703073[Crossref], [CAS], Google Scholar.259ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFClug%253D%253D&md5=c921b54ae246a3e711c7dd034e130b1cTowards the optimal screening collection. A synthesis strategyNielsen, Thomas E.; Schreiber, Stuart L.Angewandte Chemie, International Edition (2008), 47 (1), 48-56CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. The development of effective small-mol. probes and drugs entails at least three stages: (1) a discovery phase, often requiring the synthesis and screening of candidate compds.; (2) an optimization phase, requiring the synthesis and anal. of structural variants; (3) and a manufg. phase, requiring the efficient, large-scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while inhouse medicinal and process chemists perform the second and third development stages, resp. The coordinated planning of these activities in advance of the first small-mol. screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, were avoided with advance planning. Therefore, a challenge for synthetic chem. is to develop a new kind of chem. that yields a screening collection comprising small mols. that increase the probability of success in all three phase. Although this transformative chem. remains elusive, progress is being made. Herein, the authors review a newly emerging strategy in diversity-oriented small-mol. synthesis that may have the potential to achieve these challenging goals.(b) Gerry, C. J.; Schreiber, S. L. Chemical probes and drug leads from advances in synthetic planning and methodology. Nat. Rev. Drug Discovery 2018, 17, 333– 352, DOI: 10.1038/nrd.2018.53[Crossref], [PubMed], [CAS], Google Scholar259bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsFCnsbs%253D&md5=cb42a063221707b3bf60710ffd62e564Chemical probes and drug leads from advances in synthetic planning and methodologyGerry, Christopher J.; Schreiber, Stuart L.Nature Reviews Drug Discovery (2018), 17 (5), 333-352CODEN: NRDDAG; ISSN:1474-1776. (Nature Research)A review. Screening of small-mol. libraries is a productive method for identifying both chem. probes of disease-related targets and potential starting points for drug discovery. In this article, we focus on strategies such as diversity-oriented synthesis that aim to explore novel areas of chem. space efficiently by populating small-mol. libraries with compds. contg. structural features that are typically under-represented in com. available screening collections. Drawing from more than a decade's worth of examples, we highlight how the design and synthesis of such libraries have been enabled by modern synthetic chem., and we illustrate the impact of the resultant chem. probes and drug leads in a wide range of diseases.
- 260Dömling, A.; Wang, W.; Wang, K. Chemistry and biology of multicomponent reactions. Chem. Rev. 2012, 112, 3083– 135, DOI: 10.1021/cr100233r[ACS Full Text], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xkt1ehsbg%253D&md5=09577e3204db313fdb16807df21ab724Chemistry and Biology Of Multicomponent ReactionsDomling, Alexander; Wang, Wei; Wang, KanChemical Reviews (Washington, DC, United States) (2012), 112 (6), 3083-3135CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. The authors discuss the usefulness of multicomponent reactions (MCR) in medicinal chem. for drug discovery purposes. An advantage of MCR chem. is the very large chem. space, probably the largest available chem. space for drug discovery and medicinal chem. purposes. This also poses very high demands for the right choice of the discovery strategy, for example, high throughput screening or structure-based design. A promising and complementary strategy which leverages the strength of MCR chem. is the use of computation screening and genetic algorithms. In addn., MCRs can be of great value in natural product total synthesis.
- 261Wagner, B. K.; Schreiber, S. L. The power of sophisticated phenotypic screening and modern mechanism-of-action methods. Cell Chem. Biol. 2016, 23, 3– 9, DOI: 10.1016/j.chembiol.2015.11.008[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XntlSqsb4%253D&md5=e3219e156466fa5a32b2cb4bf6869a90The Power of Sophisticated Phenotypic Screening and Modern Mechanism-of-Action MethodsWagner, Bridget K.; Schreiber, Stuart L.Cell Chemical Biology (2016), 23 (1), 3-9CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)The enthusiasm for phenotypic screening as an approach for small-mol. discovery has increased dramatically over the last several years. The recent increase in phenotype-based discoveries is in part due to advancements in phenotypic readouts in improved disease models that recapitulate clin. relevant biol. in cell culture. Of course, a major historical barrier to using phenotypic assays in chem. biol. has been the challenge in detg. the mechanism of action (MoA) for compds. of interest. With the combination of medically inspired phenotypic screening and the development of modern MoA methods, we can now start implementing this approach in chem. probe and drug discovery. In this Perspective, we highlight recent advances in phenotypic readouts and MoA detn. by discussing several case studies in which both activities were required for understanding the chem. biol. involved and, in some cases, advancing toward clin. development.
- 262Churcher, I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones?. J. Med. Chem. 2018, 61, 444– 452, DOI: 10.1021/acs.jmedchem.7b01272[ACS Full Text], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvVWqtbvJ&md5=e60f1777de8bd860c5001137d8583f1fProtac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?Churcher, IanJournal of Medicinal Chemistry (2018), 61 (2), 444-452CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. Targeted protein degrdn., using bifunctional small mols. (Protacs) to remove specific proteins from within cells, has emerged as a novel drug discovery strategy with the potential to offer therapeutic interventions not achievable with existing approaches. In this perspective, the brief history of the field is surveyed from a drug discovery perspective with a focus on the key advances in knowledge which have led to the definition and exemplification of protein degrdn. concepts, and their resulting applications to medicine discovery. The approach has the potential to bring disruptive change to drug discovery - the many potential advantages and outstanding challenges which lie ahead of this technol. are discussed.
- 263(a) Murcko, M. A. What makes a great medicinal chemist? A personal perspective. J. Med. Chem. 2018, 61, 7419– 7424, DOI: 10.1021/acs.jmedchem.7b01445[ACS Full Text.], [CAS], Google Scholar263ahttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXpt12hs7k%253D&md5=375f41f1b14993861de36b2a1e69152fWhat Makes a Great Medicinal Chemist? A Personal PerspectiveMurcko, Mark A.Journal of Medicinal Chemistry (2018), 61 (17), 7419-7424CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Although it is extremely challenging to invent new medicines, I have obsd. that certain behaviors seem to be commonly found among successful medicinal chemists. Those who exhibit most of these character traits are far more likely to bring new drugs into the clinic and onto the market. And, importantly, organizations that encourage these behaviors are far more likely to be successful. These traits can be broken into two categories: "general" and "discipline-specific". General traits are those that are common to all great scientists, while the discipline-specific ones are more specialized behaviors relevant to the medicinal chem. enterprise. I describe these traits, and include some specific examples for each of the medicinal chem. characteristics that I hope will be illustrative. While success in drug discovery is never guaranteed, I believe that embracing and encouraging these behaviors increase the probability of a successful outcome.(b) Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. What do medicinal chemists actually make? A 50-year retrospective. J. Med. Chem. 2011, 54, 6405– 6416, DOI: 10.1021/jm200504p[ACS Full Text], [CAS], Google Scholar263bhttps://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFWjsr7O&md5=33109f9d55967be0d34f377f433621e4What Do Medicinal Chemists Actually Make? A 50-Year RetrospectiveWalters, W. Patrick; Green, Jeremy; Weiss, Jonathan R.; Murcko, Mark A.Journal of Medicinal Chemistry (2011), 54 (19), 6405-6416CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Despite the dramatically increasing costs of pharmaceutical R&D productivity, as measured by the no. of new drugs approved each year, has languished during the past decade. Many different explanations have been proposed to account for this decline, such as increasing regulatory scrutiny, the inherent inefficiency of very large organizations, the pursuit of highly speculative targets identified from genomics, and more objective decision-making about advancing marginal compds. into latest age clin. trials. Another factor often cited to help explain low pharmaceutical productivity is that, paradoxically, many compds. synthesized by medicinal chemists are not "druglike", at least as measured by various criteria. The authors discuss the past, present and perspectives in the development of medicinal chem.
- 264Zhang, P.; Huang, H.; Banerjee, S.; Clarkson, G. J.; Ge, C.; Imberti, C.; Sadler, P. J. Nucleus-targeted organoiridium-albumin conjugate for photodynamic cancer therapy. Angew. Chem., Int. Ed. Engl. 2019, 58, 2350, DOI: 10.1002/anie.201813002[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cnitlentg%253D%253D&md5=edb3086d8106864d0d53be83a1592c86Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer TherapyZhang Pingyu; Ge Chen; Zhang Pingyu; Huang Huaiyi; Banerjee Samya; Clarkson Guy J; Imberti Cinzia; Sadler Peter J; Huang HuaiyiAngewandte Chemie (International ed. in English) (2019), 58 (8), 2350-2354 ISSN:.An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high (1) O2 quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC50 ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
- 265Hoffer, L.; Voitovich, Y. V.; Raux, B.; Carrasco, K.; Muller, C.; Fedorov, A. Y.; Derviaux, C.; Amouric, A.; Betzi, S.; Horvath, D.; Varnex, A.; Collette, Y.; Combes, S.; Roche, P.; Morelli, X. Integrated strategy for lead optimization based on fragment growing: The diversity-oriented-target-focused-synthesis approach. J. Med. Chem. 2018, 61, 5719– 5732, DOI: 10.1021/acs.jmedchem.8b00653[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtFSrtLrK&md5=0e5f18636e2b1df24314efa81e67e2b5Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis ApproachHoffer, Laurent; Voitovich, Yuliia V.; Raux, Brigitt; Carrasco, Kendall; Muller, Christophe; Fedorov, Aleksey Y.; Derviaux, Carine; Amouric, Agnes; Betzi, Stephane; Horvath, Dragos; Varnek, Alexandre; Collette, Yves; Combes, Sebastien; Roche, Philippe; Morelli, XavierJournal of Medicinal Chemistry (2018), 61 (13), 5719-5732CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chem. probes consisting of a focused-chem.-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chem. reactions carefully chosen from a list of one-step org. transformations relevant in medicinal chem. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compds. with improved affinity by several orders of magnitude.
- 266Fleming, N. How artificial intelligence is changing drug discovery. Nature 2018, 557, S55– S57, DOI: 10.1038/d41586-018-05267-x[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtVGnt7bN&md5=b7c931ada12c78c8af7e492f9e994f22How artificial intelligence is changing drug discoveryFleming, NicNature (London, United Kingdom) (2018), 557 (7707), S55-S57CODEN: NATUAS; ISSN:0028-0836. (Nature Research)Machine learning and other technologies are expected to make the hunt for new pharmaceuticals quicker, cheaper and more effective.
- 267Schneider, G. Automating drug discovery. Nat. Rev. Drug Discovery 2017, 17, 97– 113, DOI: 10.1038/nrd.2017.232